Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments

ABSTRACT

This invention relates to new generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, to their optical isomers, diastereomers or enantiomers, as well as pharmaceutically acceptable salts, hydrates, prodrugs, polymorphs and pseudopolymorphs thereof, to their preparation, to their compositions and to their use.

This application is a continuation-in-part of copending application Ser.No. 10/128,996 filed on Apr. 23, 2002. The nonprovisional applicationdesignated above, namely application Ser. No. 10/128,996, filed Apr. 23,2002, claims the benefit of U.S. Provisional Application No. 60/286,291filed on Apr. 25, 2001, and claims the benefit of U.S. provisionalapplication No. 60/341,165, filed Dec. 13, 2001.

FIELD OF THE INVENTION

The present invention relates to novel antimicrobial 7-substitutedpiperidino-quinolone carboxylic acid derivatives and pharmaceuticallyacceptable salts thereof. Methods of preparation of the compounds of theinvention, compositions of compounds of the invention and their use arealso described.

BACKGROUND OF THE INVENTION

The fluoroquinolone group of antibiotics available since the early 1960sare valuable as antibacterial agents. There have been synthesized,developed and marketed quinolone carboxylic acid derivatives havingvarious chemical structures. Nalidixic acid, the progenitor of theseries, was used primarily as a urinary tract antiseptic. Laterdevelopment provided agents with broader activity, increased potencyagainst selected pathogens and improved pharnacokinetic andpharmacodynamic properties.

From a medical utility viewpoint, the quinolones are classified asfirst-, second-, and third-generation compounds (Gootz T D et al,Chemistry & Mechanism of Action of the Quinolone Antibacterials. InAndriole VT ed. The Quinolones, San Francisco, Academic Press, 1998,28-80). First-generation compounds like piromidic acid and pipemidicacid provided coverage for gram-negative Enterobacteriaceae. Thesecond-generation compounds are divided into those with enhanced butpredominant gram-negative activity, against pathogens like Escherischiacoli and Pseudomonas aeruginosa, and those with balanced broad-spectrumactivity (norfloxacin, pefloxacin, enoxacin, fleroxacin, lomefloxacin,ciprofloxacin, ofloxacin, rufloxacin, nadifloxacin). Norfloxacin,ofloxacin and ciprofloxacin have, therefore, been used mainly fortreatment of diseases including urinary tract infections,gastrointestinal infections, sexually transmitted diseases and the like.Third-generation drugs (levofloxacin, pazufloxacin, sparfloxacin,clinafloxacin, sitafloxacin, trovafloxacin, tosufloxacin, temafloxacin,grepafloxacin, balofloxacin, moxifloxacin, gatifloxacin) are those withenhanced activity against gram-positive cocci (notably clinafloxacin,sitafloxacin, trovafloxacin for Streptococcus pneumoniae) and, foressentially all the third-generation quinolones, activity also againstgram-negative Haemophilus influenzae and Legionella pneumophila, andagainst anaerobes and atypical pathogens (Ball P, The Quinolone. Historyand Overview. In Andriole VT ed. The Quinolones, San Francisco, AcademicPress, 1998, 1-28). Levofloxacin, moxifloxacin and gatifloxacin have,therefore, found use for community-acquired infections such as those ofthe upper and lower respiratory tract infections (RTI) like pneumonia,sinusitis and pharyngitis, and for skin and soft tissue infections (SSI)caused by gram-positive strains of staphylococci, pneumococci,streptococci and enterococci.

The improvements seen in most of the third-generation drugs in currentuse are generally attributed to their uniqueness in inhibiting thebacterial targets, DNA gyrase and topoisomerase IV. Three categories ofquinolone inhibition have been suggested. Type I quinolones(norfloxacin, enoxacin, fleroxacin, ciprofloxacin, lomefloxacin,trovafloxacin, grepafloxacin, ofloxacin and levofloxacin) indicated apreference for topoisomerase IV inhibition. Type II quinolones(nadifloxacin and sparfloxacin) indicated a preference for DNA gyraseinhibition. Type III quinolones to which some of the third-generationquinolones belong (gatifloxacin, pazufloxacin, moxifloxacin andclinafloxacin) display, however, a dual-targeting property, and equallyinfluence DNA gyrase inhibition and topoisomerase IV inhibition. (TakeiM et al, Antimicrobial Agents and Chemotherapy, 2000; 45:3544-49). DNAgyrase is the primary target in bacteria, and thus is explained theweaker activity in gram-positive bacteria of the preferred topoisomeraseIV-targeting second-generation quinolones like norfloxacin,ciprofloxacin, ofloxacin, and levofloxacin. The unusual activity ofnadifloxacin described by others, and further significantly elaboratedfor S-(−)-nadifloxacin by us (cf: our pending U.S. application Ser. No.09/566,875, 09/850,669, WO 00/68229 and WO 01/85728), specially againstgram positive S. aureus, is now better understood in view of its beingshown to be DNA-gyrase targeting, which is the first such report for aquinolone in S. aureus (Oizumi N et al, J. Infect. Chemother, 2001; 7:191-194). Some, but not all, third generation quinolones being primarilytopoisomerase IV-targeting in gram-positive staphylococci, and DNAgyrase-targeting in gram-positive S. pneumoniae, explains the advantagesprovided by the dual-targeting third-generation quinolones likemoxifloxacin and gatifloxacin.

The evolution of quinolones from first-generation to second-generationto third-generation compounds has also been guided by structure-activityrelationship studies. It has been determined by those in the art thatcertain structures with specific sites on the quinolone ringfunctionalised have distinct advantages over others. Structure-activityrelationships of the quinolones have been the subject of detailed studyfor more than a decade (Asahina Y et al, Recent Advances in StructureActivity Relationships in New Quinolones, Prog. Drug Res., 1992, 38,57-106) As a result of these studies, it has been determined by those inthe art that certain structures, with specific sites on the quinolonering functionalised, have distinct advantages over others. Thestructural feature that remains constant throughout the drug class isthe bicyclic aromatic core consisting of 2 fused 6-membered rings. Thiscore can contain a carbon at the 8-position, yielding a true quinolone,or a nitrogen which provides a ring system technically termed anaphthyridone, or an additional fused ring across the N-1 and C-8positions yielding tricyclic heterocycles, such as pyridobenzoxazinesand benzoquinolizidines.

In the context of the current invention, the nature of the amine groupat the 7-position takes on special relevance. It is notable that in thecited second-generation quinolones the piperazine ring remainsrelatively constant and undisturbed as a 7-substituent, except foralkylation on the distal nitrogen, or less frequently on the ringcarbons. In the third-generation quinolones, the continuing trend of useof a C-7 cyclic amino group is also almost universal. The presence of asecond amine, in addition to the nitrogen bonded to C-7 of the quinolonenucleus has been found to be important. However, amongst these newquinolones, too, the frequent employment of mainly a C-7 piperazino orpyrrolidino variant is to be noted, but with only one example of a C-7piperidino substituent.

Only two of the above-cited quinolones, the second-generationnadifloxacin and the third-generation balofloxacin, have a C-7piperidino substituent. Nadifloxacin with a hydroxypiperidinesubstituent at the C-7 position is notable for its being the solemarketed modern quinolone without a distal amino group, but is merely atopical agent. Balofloxacin has an unusual 3-methylaminopiperidinosubstituent, which is, however, said to be the contributing element toits lower activity against Enterobacteriaceae and Mycoplasma pneumoniae.Among the recent fluoroquinolones which have been introducedcommercially are moxifloxacin and gatifloxacin. Both these antibacterialagents have an 8-methoxy substituent in the fluoroquinolone core. As7-substituents in the core, there is for moxifloxacin a bicyclicpyrollidine as the amino moiety, and for gatifloxacin a substitutedpyrollidine as the amino moiety. A more recently describedolamufloxacin, which has been shown to have activity in murine models ofsystem infections and urinary tract infections, has an 8-methylsubstituent in its fluoroquinolone core in which the C-7 substituent isalso a substituted pyrollidine. No commercially introducedfluoroquinolone or one that has commercial potential is known in which apiperidino group, substituted or unsubstituted, is introduced at the7-position of the quinolone structure also having a methoxy group ormethyl group at the 8-position.

Since the 1960s, in an enormous worldwide effort, well more than 10,000structurally-related fluoroquinolone agents have been described in manyhundreds of patents and journal articles. Despite the understanding ofthe need of a cyclic amine at the C-7 position, the prior art appears tohave discounted the value of having a piperidino moiety, unsubstitutedor substituted, as a C-7 substituent. For instance, a 1992 reviewarticle (Asahina Y et al, vide infra) indicates the comparative lowprior art interest in C-7 piperidino substituents, wherein there areonly 21 piperidino moieties cited in comparison to 188 piperazinomoieties, and 74 pyrollidino moieties out of a total of 578 C-7 aminomoieties.

Just as there are structure-activity relationships, there are alsostructure-side effect relationships that have been determined. Sideeffects and adverse events related to N-1, C-5, C-8 variants of thequinolone core are generally those that contribute to increase intheophylline interactions, clastogenicity, phototoxicity,hepatotoxicity, cardiotoxicity, arthropathy and tendonitis. Notable isthe pattern of (a) the N-1 cyclopropyl and C-8 fluorine, chlorine ormethoxy substituted quinolone reported to show heightened cytotoxicity(Domagala J M, J. Antimicrob. Chemother., 1994; 33: 655-706), which canbe modulated, however, by further structural manipulation (Gootz T D etal, vide infra), (b) the presence of halogen atoms (fluorine orchlorine) at the C-8 position (sparfloxacin, clinafloxacin) enhancingthe tendency to induce photosensitivity, (c) the N-1 difluorophenylsubstituent in trovafloxacin and temafloxacin associated withhepatotoxicity and hemolytic anemia and (d) the C-5 methyl(grepafloxacin) and C-8 methoxy substituent (moxifloxacin, gatifloxacin)contributing to prolongation of the QT interval and the development of aform of ventricular tachycardia known as torsade de pointes.

As important, if not more so, than the above-mentioned substituents ofthe fluoroquinolone core is the amine substituent at the C-7 site. C-7pyrrolidines tend to show increased cytotoxicity over piperazinosubstituents, with the combination of 3-substituted pyrrolidines at C-7and halogens at C-8 providing the most cytotoxic compounds.(Suto N J etal, J Med Chem 1992; 35:4745-50; Mundell L A et al, Clin Infect Dis,2001; 32(Suppl): S74) In the second most frequently encountered form ofquinolone toxicity, namely adverse events involving the CNS, it is theunsubstituted piperazines which correlate best with the degree ofGABA-binding inhibition, closely followed by the pyrrolidinylquinolones.

The incremental improvements that have resulted in moving from first- tosecond- and third-generation quinolones are a consequence of theunderstanding of the modulation brought about by a combination of afluoroquinolone core moiety with a C-7 amino substituent. Althoughcertain substituents can impart improvements, whether on one hand inantibacterial potency or on the other in a minimised potential foradverse effect, it is the overall characteristics of each moleculederived from the interaction of all the substituents with each other andwith the specific nucleus employed that brings newer gains. Furthermore,characteristics in addition to those of activity and side effects arecentral to the development of improved human theraputants such asselective molecular mechanisms of action, broader antibacterial coverageto include anaerobes, atypical and resistant pathogens, improvedpharmacokinetics and pharmacodynamics, and devoid of class-identifiedtoxicity features.

It is, thus, clear that the art has focussed on identifying newquinolones to progress from earlier generation compounds to the nextgeneration compounds. Despite the progress made, the full promise of thequinolones has not yet been exploited.

Examples of bacterial infections resistant to antibiotic therapy havebeen reported in the past; they are now a significant threat to publichealth in the developed world. The development of microbial resistanceis of increasing concern in medical science. “Resistance” can be definedas existence of organisms, within a population of a given microbialspecies, that are less susceptible to the action of a givenantimicrobial agent. This resistance is of particular concern inenvironments such as hospitals and nursing homes, where relatively highrates of infection and intense use of antibacterials are common. Recentinternational conferences in 2002 on infectious diseases organised bythe Centres for Disease Control and Prevention, USA, World HealthOrganisation and other groups have highlighted emerging infectiousdiseases, in which the word “emerging” refers to newly discoveredinfectious diseases or old ones that have rebounded, turned up in newplaces, or become drug resistant.

The mechanisms of bacterial resistance to fluoroquinolones is generallybelieved to function by two principal categories, both resulting fromchromosomal mutations (D C Hooper, Drug Resis Updat 1999; 2:38-55). Onecategory is the alterations in drug target enzymes. Fluoroquinoloneresistance mutations generally occurring stepwise have been localized tospecific regions of the parC and parE genes (grlA and grlB in S. aureus)encoding topoisomerase IV, and the gyrA and gyrb genes encoding DNAgyrase. This clustering of mutations has defined the quinoloneresistance determining regions (QRDRs) of these genes that are inproximity to the apparent enzyme active site and are thought likely toconstitute a domain at which quinolones interact directly with theenzyme-DNA complex. The manner by which the emergence of resistantmutants can be prevented is receiving attention, but is as yetinsufficiently understood and continues to be speculative. Studies withthe C-8 methoxy fluoroquinolones bearing a C-7 unsubstituted or 3-alkylsubstituted piperazino substituent provide support to the concept thatattack of both gyrase and topoisomerase IV equally would be ideal. Incases where single point mutation already exists, then a quinolone thatwould preferably potently inhibit the primary more essential target,whether gyrase or topoisomerase IV, would be better to prevent theresistance (Zhao et al, Proc. Natl. Acad. Sc. 1997; 94: 13991-13996). Nosimilar study, to our knowledge, is available for compounds with a C-7piperidino substituent, whether unsubstituted or substituted, in anyquinolone core. The second category for bacterial resistance to developis alterations that limit permeation of drug to the target. In S. aureusthe elevated expression of the norA gene is responsible forefflux-mediated resistance to quinolones. Factors influencing thedecrease in activity of quinolones in efflux-mediated resistant mutantsof S. aureus have been suggested not to be hydrophobicity of the wholequinolone molecule, but rather the bulkiness at the C-7 substituent, andbulkiness and hydrophobicity at the C-8 substituent (Takenouchi T et al,1996; 40:1835-42). Only two of forty quinolones included in thisanalysis bore a C-7 amino-substituted piperidino substituent. The effectof efflux was more pronounced with the compound bearing the 4-aminosubstituted piperidino substituent, its MIC value being 8 times morewith an efflux pump-bearing strain than with a non-efflux pump-bearingstrain, as compared with a 2 times more value for the 3-aminosubstituted piperidino substituent. Surprisingly, unlike this precedent,the present invention shows that appropriately substituted 4-aminopiperidine substituents on different fluoroquinolone cores displaypotent efflux pump inhibitory/uptake facilitatory properties.

Stereochemistry-activity relationships are also of importance inconsiderations regarding the advancement of quinolones that can exist asisomers. For instance, S-(−)-levofloxacin, as an example of a compoundin which the chiral centre is close to the quinolone nucleus, is from8-128 fold as potent as the R-(+)-enantiomer. Earlier work and ourpending U.S. patent application Nos. 09/566,875 and 09/850,669, WO00/68229 and WO 01/85728 on nadifloxacin, which like levofloxacin has arelatively similar chiral centre, also disclose the superior profile ofS-(−)-nadifloxacin over the R-(+)-enantiomer. Chiral centres at C-7 thatare at some distance from the quinolone nucleus are said to contributeless significantly to biological activity. However, the relativeorientation of the methyl groups on the C-7 piperazine of sparfloxacinis important for bacterial enzymes versus mammalian enzyme selectivity.Sparfloxacin, bearing methyl groups with a cis-stereochemistry essentialfor its antibacterial activity, displays dramatic differential effectson mammalian topoisomerase-II with no or less interaction with themammalian enzyme, in contrast to the trans-isomer which does interactwith the mammalian enzyme, while however retaining its antibacterialactivity (Gootz T D et al., vide infra). Unlike this prior art, thepresent invention once again surprisingly shows that stereochemicaldifferences of substituents on the C-7 piperidino moiety, whiledramatically affecting antibacterial activity, do not significantlyinfluence cytotoxicity of mammalian cell lines, irrespective of whetherthe differences are enantiomeric or diastereomeric.

Both of the third-generation fluoroquinolone market introductions ofmoxifloxacin and gatifloxacin with improved activity againstgram-positive pathogens, have an 8-methoxy substituent in the corefluoroquinolone nucleus. Even their coverage, however, of staphylococciis considered partial, as they possess weak antibacterial activityagainst most of the methicillin-resistant strains. Moreover,moxifloxacin and gatifloxacin have failed to show therapeuticallyrelevant potency for recent widely reported ciprofloxacin-resistant andlevofloxacin-resistant strains of pneumococci. In addition, the potencyof newer fluoroquinolones such as moxifloxacin against gram-negativepathogenic bacteria such as E. coli and P. aeruginosa has considerablydiminished.

Therefore, there is a need for newer orally effective fluoroquinoloneantibacterials with superior potency not only againstmethicillin-resistant, macrolide-resistant and fluoroquinolone-resistantstrains, viz. multidrug-resistant strains of gram-positive staphylococciand pneumococci, but also against gram-negative strains with potencycomparable to ciprofloxacin and levofloxacin, and against the now socalled emerging infectious diseases. Accordingly, numerous studies arebeing continuously conducted to address the disadvantages of thefluoroquinolones having an 8-methoxy substituent or 8-alkyl substituentor other 8-substituents to make them considerably more potent againstbacterial pathogens, to increase their spectrum coverage to include theinsufficiently addressed pathogens like mycobacteria, anaerobes, andatypicals, to optimise their action towards bacterial molecular targets,to reduce their efflux or facilitate their cellular uptake, and toimprove their oral bioavailability and toxicity profile.

Some 1,4-dihydroquinolone related moieties bearing an 8-methoxysubstituent are known in the art to have antimicrobial activity and aredescribed in the following references:

U.S. Pat. No. 4,638,067 to Culbertson, et al. on Jan. 20, 1987; U.S.Pat. No. 4,665,079 to Culbertson, et al. on May 12, 1987; EuropeanPatent Application 0230295A2 of Kyorin Pharmaceutical Co. pub. Jul. 29,1987; European Patent Application 0241206A2 of Ube Ind pub. Oct. 14,1987; U.S. Pat. No. 4,822,801 to Domagala et al. on Apr. 18, 1989; U.S.Pat. No. 509 7032 to Domagala et al. on Mar. 17, 1992; U.S. Pat. No.5,051,509 to Nagano et al. on Sep. 24, 1991; European Patent Application0541086A1 of Kaken Pharmaceutical Co. published May 12, 1993; EuropeanPatent Application 0572259A1 of Ube Ind. Published Dec. 1, 1993; WO1993-JP 1925 of Japan Tobacco, Inc., dated Dec. 28, 1993; EuropeanPatent Specification 0342675B1 of Chugai Seiyaku Kabushiki Kaishapublished Jan. 25, 1995; Japanese Patent 6-145167 published May 24,1994; U.S. Pat. No. 5,607,942 of Clive Petersen et al. on Mar. 4, 1997;PCT patent application No. PCT/KR94/00005 to Korea Research Institute ofChemical Technology published Jul. 21, 1994; U.S. Pat. No. 5,677,316 toHideki et al. on Oct. 14, 1997; World Patent WO98/58923A1 to Hagano etal. on Jun. 23, 1998; U.S. Pat. No. 4,777,175 to Warner-Lambert Co. onOct. 11, 1988; European Patent Application 0919553A1 of Daiichi PharmaCo. published Jun. 2, 1999; U.S. Pat. No. 6,121,285 to Takemura et al.,on Sep. 19, 2000; U.S. Pat. No. 6,329,391 B1 to Benoit Ledoussel et al.On Dec. 11, 2001.

Similarly some 1,4-dihydroquinolone related moieties bearing an 8-alkylsubstituent, in particular an 8-methyl substituent, are known in the artto have antimicrobial activity and are described in the followingreferences: U.S. Pat. No. 4,874,764 to Hiraki Ueda et al., on Oct. 17,1989; U.S. Pat. No. 4,935,420 to Hiraki Ueda et al., on Jun. 19, 1990,U.S. Pat. No. 5,859,026 to Ito et al., on Jan. 12, 1999 and EuropeanPatent application 0919553A1 of Daichi Pharmaceutical Company publishedJun. 2, 1999; U.S. Pat. No. 6,121,285 to Takemura et al., on Sep. 19,2000.

The methods of producing quinolone carboxylic acids bearing an 8-methoxysubstituent are also to be found in the following references:

U.S. Pat. No. 5,639,886 to Zerbes et al. on Jun. 17, 1997; U.S. Pat. No.5,869,661 to Ochi et al. on Feb. 9, 1999; and PCT Patent Application No.WO 99/26940 to Bayer Aktiergesellschaft published Jun. 3, 1999.

The methods of producing quinolone carboxylic acids bearing an 8-methylsubstituent are also to be found in the following references: U.S. Pat.No. 5,859,026 to Ito et al., on Jan. 12, 1999; U.S. Pat. No. 6,121,285to Takemura et al., on Sep. 19, 2000.

European Patent application 0919553A1 of Daichi Pharmaceutical Companypublished Jun. 2, 1999.

A number of compounds having a cyclic amino moiety as substituents atthe 7-position of these quinolone carboxylic acids are already known. Inaddition, many attempts have been made to modify the 7-cyclic aminomoiety with various substituents to produce superior compounds, and, forexample, a cyclic amino substituent such as 4-amino-1-piperidinyl groupor 4-hydroxy-1-piperidinyl group wherein the adjacent carbon atom to theamino or hydroxy substituent is further monosubstituted by an alkylsubstituent is known, as hereinbelow described in the identified patentapplications and patents.

For example PCT patent application WO 99/14214 and U.S. Pat. No.6,329,391B1 discloses a compound having a cyclic amino substituent ofthe formula

wherein each symbol is as defined in the specification of theabove-mentioned publication. For the piperidino substituent at the7-position of the quinolonecarboxylic acid, the compounds havingsubstituents of 3-amino-4-methyl, 3-amino-4-4-dimethyl,3-amino-4-spirocyclopropyl, 3-amino-6-cyclopropyl, are included in thepreferred examples therein. However, specific examples of compoundshaving a substituent at the 7-position as piperidine of the presentinvention with a 4-amino or 4-hydroxy substituent with 2-alkyl, 3-alkyl,5-alkyl or 6-alkyl substituents, or with geminal 3,3-dialkyl, or3,5dialkyl, or 3,3,5-trialkyl substituents, located at a positionadjacent to the substituent at the 4-position, are not disclosed. Whatis more, compounds with a piperidine substituent at the 7-position asdefined in the cited patent application above with a substituent in the8-position as a methoxy group (R₈=OCH₃) or as an alkyl group (R₈=CH₃,C₂H₅) and the substituent in the 6-position as a fluoro group (R₆=F) arealso not disclosed.

European Patent Application 241206A2 discloses a compound having a7-cyclic amino substituent of the formula

with one meaning of Y being

wherein each symbol is as defined in the specification of theabove-mentioned publication at the 7-position of quinolonecarboxylicacid and the compounds having substituents of 4-hydroxy-3-methyl,4-amino-3-methyl, or 4methylamino-3-methyl are included as specificexamples therein. However, specific examples of the compounds having asubstituent at the 7-position as piperidine of the present inventionwith a 4-amino or 4-hydroxy substituent with 2-alkyl or 6-alkylsubstituents, or with 3,3-dialkyl substituents, geminally located at aposition adjacent to the substituent at the 4-position are notdisclosed.

European Patent Application 0394553B1 discloses a compound for thetreatment of HIV infections having a 7-cyclic amino substituent of theformula

wherein each symbol is as defined in the specification of theabove-mentioned publication at the 7-position of the quinolonecarboxylic acid with a 4-amino substituent and a single 3-alkylsubstituent or a 3-3-dialkyl substituent claimed. However, specificexamples of the compounds having a substituent at the 7-position aspiperidine of the present invention with a 4-amino or 4-hydroxysubstituent with 2-alkyl, 3-alkyl, 5-alkyl or 6-alkyl substituents, orwith geminal 3,3-dialkyl, or 3,5-dialkyl, or 3,3,5-trialkylsubstituents, located at a position adjacent to the substituent at the4-position are not disclosed. What is more, compounds with a piperidinesubstituent at the 7-position as defined in the cited patent applicationabove with a substituent in the 8-position as a methoxy group (Q=C—OCH₃)or as an alkyl group (Q=C—CH₃, C—C₂H₅) are also not disclosed.

European Patent Application 0304087A2 discloses a compound having a7-cyclic amino substituent of the formula

wherein each symbol is as defined in the specification of theabove-mentioned publication at the 7-position of the quinolonecarboxylic acid with a 4-amino substituent and a single 3-alkylsubstituent is claimed. However, specific examples of compounds having asubstituent at the 7-position as piperidine of the present inventionwith a 4-amino or 4-hydroxy substituent with 2-alkyl, 3-alkyl, 5-alkylor 6-alkyl substituents, or with germinal 3,3-dialkyl, or 3,5-dialkyl,or 3,3,5-trialkyl substituents, located at a position adjacent to thesubstituent at the 4-position are not disclosed. What is more, compoundswith a piperidine substituent at the 7-position as defined in the citedpatent application above with a substituent in the 8-position as amethoxy group (X=C—OCH₃) or as an alkyl group (X=C—CH₃, C—C₂H₅) are alsonot disclosed.

European Patent Application 0572259A1 discloses a compound having a7-cyclic amino substituent of the formula

wherein each symbol is as defined in the specification of theabove-mentioned publication at the 7-position of the quinolonecarboxylic acid with a 4-amino piperidinyl moiety wherein the aminogroup is substituted with an aryl or aromatic hetero monocyclic group ora fused aromatic group and a single 3-alkyl substituent is disclosed.However, specific examples of compounds having a substituent at the7-position as piperidine of the present invention with a 4-amino or4-hydroxy substituent with 2-alkyl, 3-alkyl, 5-alkyl or 6-alkylsubstituents, or with geminal 3,3-dialkyl, or 3,5-dialkyl, or3,3,5-trialkyl substituents, located at a position adjacent to thesubstituent at the 4-position are not disclosed. What is more, compoundswith a piperidine substituent at the 7-position as defined in the citedpatent application above with a substituent in the 8-position as amethoxy group (X=C—OCH₃) or as an alkyl group (X=C—CH₃, C—C₂H₅) are alsonot disclosed.

European Patent Application 0287951A2 discloses a compound having a7-cyclic amino substituent as in the following formula

in which one of the meanings of R₂ is substituent which is a 5- to9-membered saturated or unsaturated heterocyclic ring which may besubstituted, wherein each symbol is as defined in the specification ofthe above-mentioned publication at the 7-position of the quinolonecarboxylic acid with a 4-hydroxy piperidinyl moiety. However, specificexamples of compounds having a substituent at the 7-position aspiperidine of the present invention with a 4-amino or 4-hydroxysubstituent with 2-alkyl, 3-alkyl, 5-alkyl or 6-alkyl substituents, orwith geminal 3,3-dialkyl, or 3,5-dialkyl, or 3,3,5-trialkylsubstituents, located at a position adjacent to the substituent at the4-position are not disclosed. What is more, compounds with a piperidinesubstituent at the 7-position as defined in the cited patent applicationabove with a substituent in the 8-position as a methoxy group (R₃=OCH₃)or as an alkyl group (R₃=CH₃, C₂H₅) are also not disclosed.

U.S. Pat. No. 4,382,892 discloses a compound having a cyclic substitutedamino group

which is a 4- to 7-membered ring which may be substituted, wherein eachsymbol is as defined in the specification of the above-mentionedpublication at the Z substituted position of the quinolone carboxylicacid with a 4-amino 1-piperidinyl moiety, 4-dimethylamino 1-piperidinylmoiety and 4-hydroxy 1-piperidinyl moiety.

However, specific examples of compounds having a substituent at the7-position as piperidine of the present invention with a 4-amino or4-hydroxy substituent with 2-alkyl, 3-alkyl, 5-alkyl or 6-alkylsubstituents, or with geminal 3,3-dialkyl, or 3,5-dialkyl, or3,3,5-trialkyl substituents, located at a position adjacent to thesubstituent at the 4-position are not disclosed.

The feature of the known 7-substituted piperidino derived compounds isthat they are said to exhibit antimicrobial properties, but either nobiological data is provided or in cases where some data is provided,such piperidino derivatives have been found to be inferior in activityto those derivatives bearing 7-piperazino or 7-pyrrolidino substituents.It is only through our on-going studies in recent years as described inour pending U.S. patent application Ser. Nos. 09/566,875 and 09/850,669,WO 00/68229 and WO 01/85728 that there has begun to be elaborated thefull potential of a fluoroquinolone core bearing an unsubstituted orsubstituted 4-hydroxy piperidino substituent at the 7^(th) position ofthe core fluoroquinolone for use in clinical development as medicamentsfor life-threatening old and new emerging infectious diseases.

Thus, the present inventors have extensively studied the subject byintroducing various substituted piperidine groups in the 7-position ofdifferent fluoroquinolone cores and determining themicrobiological/pharmacological properties of the compounds to developthe novel substituted piperidino compounds of the invention, which (a)show a potent hitherto-undescribed antibacterial potency against broadspectrum sensitive and existing/emerging resistant pathogenic strains,including β-lactam-resistant, macrolide-resistant and evenfluoroquinolone-resistant strains, mycobacteria, anaerobes and atypicalpathogens (b) prevent selection of resistant bacteria by apparentlyinhibiting both DNA gyrase and topoisomerase IV equally, or by potentlyinhibiting the enzyme it targets, (c) are not subjected to efflux orhave facilitated uptake, (d) do not apparently act to merely formbacteriostatic quinolone-gyrase/topoisomerase-DNA complexes to inhibitcell growth, but also apparently extend the action to release the brokenDNA ends to ensure cell death, (d) exhibit high absorption and improvedpharmacokinetic properties in a living body, and (e) display afavourable safety profile. As a result, we have identified that thecompounds of the general formula I as defined below wherein substitutedpiperidino groups are introduced into the 7-position of thefluoroquinolone nucleus can satisfy such a purpose.

It is therefore, an aspect of the present invention to provide newnon-chiral and chiral 7-substituted piperidino-quinolone carboxylic acidderivatives, of the formula I, as defined below, which show potentantibacterial activity against a broad range of pathogenicmicroorganisms, including both gram-positive and gram-negative strainswith advantages of activity against resistant microorganisms, reducedtoxicity, and improved pharmacology and pharmacokinetics.

It is another aspect of the present invention to provide a process forpreparing 7-substituted piperidino-quinolone carboxylic acid derivativesof the formula I.

It is a further aspect of the present invention to prepare theintermediates that are necessary to obtain the 7-substitutedpiperidino-quinolone carboxylic acid derivatives of the formula I.

It is a further aspect of the present invention to provide compositionscontaining 7-substituted piperidino-quinolone carboxylic acidderivatives of the formula I as an active component.

It is also an aspect of the invention to use the 7-substitutedpiperidino-quinolone carboxylic acid derivatives of the formula I of theinvention and compositions containing them as medicaments for thetreatment of infectious diseases.

SUMMARY OF THE INVENTION

This invention describes fluoroquinolones of the formula I

wherein

-   -   R₁ is C₁₋₅ alkyl, substituted C₁₋₅ alkyl, C₃₋₆ cycloalkyl,        substituted C₃₋₆ cycloalkyl, aryl, or substituted aryl;    -   or when Q is CH and the nitrogen atom to which R₁ is linked        forms an optionally substituted 5-, 6- or 7-membered ring with        the carbon atom of Q, the ring optionally containing one or more        hetero atoms selected from nitrogen, oxygen or sulfur atoms,        said heteroatom(s) represented by T, preferably R₁ is CH₂CH₂—,        CH₂T—, CH₂CH₂CH₂—, CH₂CH₂T—, CH₂TCH₂—, TCH₂T—,        TCH₂CH₂CH₂CH₂—CH₂CH₂CH₂T—, CH₂TCH₂CH₂₋, or TCH₂CH₂T— where T        represents NH, O, or S. If the ring is substituted, the        substituent is as defined above for R₁.    -   Y is OR₃ where    -   R₃ is hydrogen;    -   R₃ is C₁-C₂₀ alkyl, such as straight chain or branched chain        aliphatic residues;    -   R₃ is aralkyl;    -   R₃ is CH₂CH(NH₂)COOH;    -   R₃ is (CH₂)_(n)—CHR₁₀—OCOR₁₁ or (CH₂)_(n)—CHR₁₀—OCO₂R₁₁ wherein        R₁₀ is H, or CH₃; n is 0-3 and R₁₁ is C₁-C₂₀ alkyl, substituted        C₁-C₆ alkyl or aralkyl or R₁₁ is    -   or R₃ is α-aminoalkanoyl or an alkanoylalkyl group;    -   or R₃ is    -    wherein    -   A is CH or N, and when A is CH, Z is NH or NCH₃, and when A is        N, Z is CH, O, NH, S, or NCH₃; p is 0-2; q is 0-2; or    -   Y is NHR₂, wherein R₂ is H, C₁₋₂₀ alkyl, C₃₋₆ cycloalkyl,        substituted C₃₋₆ cycloalkyl, aryl, substituted aryl, or        heteroaryl, all of which heteroaryl residues may be further        substituted or unsubstituted;    -   or R₂ is an amino acid residue derived from one of the 20        naturally occurring amino acids, or the optically active isomers        thereof, or the racemic mixtures thereof;    -   R₅ is H, C₁₋₅ alkyl, C₁₋₅ alkoxy, amino, C₁₋₅ alkylamino, or        C₁₋₅ acylamino;    -   Q is —N—, —C(R₈)— (R₈ being H, F, Cl, bromo, C₁₋₄ alkyl or        unsubstituted or substituted C₁₋₄ alkoxy, wherein when the        alkoxy group is substituted it is substituted by one or more        halogen atoms such as F, Cl, or Br),    -   or when Q is CH and the nitrogen atom to which R₁ is linked        forms an optionally substituted 5-, 6- or 7-membered ring with        the carbon atom of Q, the ring optionally containing one or more        hetero atoms selected from nitrogen, oxygen or sulfur atoms,        said heteroatom(s) represented by T, preferably R₁ is CH₂CH₂—,        CH₂T—, CH₂CH₂CH₂—, CH₂CH₂T—, CH₂TCH₂—, TCH₂T—,        TCH₂CH₂CH₂CH₂—CH₂CH₂CH₂T—, CH₂TCH₂CH₂₋, or TCH₂CH₂T— where T        represents NH, O, or S. If the ring is substituted, the        substituent is as defined above for R₁,    -   X is OR₄,    -   wherein R₄ is hydrogen, C₁-C₂₀ alkyl, glycosyl, aralkyl, C₁-C₆        alkanoyl, aminoalkanoyl or an amino acid residue derived from        one of the 20 naturally occurring amino acids, or the optically        active isomers thereof, or the racemic mixtures thereof, or R₄        is 1-aminocyclohexylcarbonyl or COOR₁₁ wherein R₁₁ is as        hereinbefore defined or R₄ is CH₂)_(n)—CHR₁₀—OCOOR₁₁ where R₁₀        and R₁₁ are as hereinbefore defined, or R₄ is C₆H₁₁O₆,        PO₂(CH₃)H, PO₃H₂, PO₂(OCH₃)H or SO₃H thus giving respectively        the gluconic acid, phosphonic acid, phosphoric acid and sulfonic        acid ester derivatives of the compounds;    -   or X is NR₆R₇.    -   wherein R₆ is H, C₁₋₂₀ alkyl, C₃₋₆ cycloalkyl, aralkyl, C₁₋₂₀        alkanoyl, C₁₋₂₀ alkoxycarbonyl, aralkyloxycarbonyl,        amino(C₁₋₂₀)alkanoyl, or an amino acid residue derived from one        of the 20 naturally occurring amino acids or the optically        active isomers thereof, or the racemic mixtures thereof.

The amino acid residue is derived from a single amino acid or fromcombinations of amino acids that form dipeptide, tripeptide orpolypeptide amino acid unit residues, wherein a terminal carboxy groupis optionally protected by C₁₋₄ alkyl or aralkyl groups and a terminalamino group is optionally protected by a ^(t)-Boc(tertiarybutyloxycarbonyl), F-Moc (fluorenylmethoxycarbonyl) or Cbz(benzyloxycarbonyl) group.

R₆ may also be COOR₁₁ wherein R₁₁ as hereinbefore defined or R₆ isC₆H₁₁O₆ thus giving the gluconic acid ester derivative of the compounds.

R₇ is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aralkyl; C₁₋₆ alkanoyl,aralkyloxycarbonyl or amino(C₁₋₂₀) alkanoyl; or an amino acid residuederived from one of the 20 naturally occurring amino acids or theoptically active isomers thereof, or the racemic mixtures thereof. Theamino acid residue is derived from a single amino acid or fromcombinations of amino acids that form dipeptide, tripeptide orpolypeptide, amino acid unit residues, wherein a terminal carboxy groupis optionally protected by C₁₋₄ alkyl or aralkyl groups and a terminalamino group is optionally protected by a ^(t)-Boc(tertiarybutyloxycarbonyl), F-Moc (fluorenylmethoxycarbonyl) or Cbz(benzyloxycarbonyl) group or R₇ may be C₆H₁O₆.

R₈/R₈′ are substituents at the 3/3-position of the piperidino ring andare the same or different and represent H, C₁₋₆ alkyl, substituted C₁₋₆alkyl, alkylamino, or aralkyl.

R₉ is a substituent at the 4-position or 5-position of the piperidinoring and represents H, C₁₋₆ alkyl, C₁₋₅ alkylamino, C₁₋₃ dialkylamino,aryl, aralkyl or a trihaloalkyl.

This invention also includes optical isomers, diastereomers,enantiomers, polymorphs, pseudopolymorphs, pharmaceutically acceptablesalts, hydrates, or biohydrolyzable esters, amides, or solvates of thefluoroquinolones of formula I and prodrugs of these compounds. Inaddition, compositions incorporating the compounds of the invention, orusing compounds of the invention as starting material are alsocontemplated in this invention.

The new compounds of the invention have increased potency andbactericidal activity that can be attributed to the combinations of therespective R₁, Y, R₅, and Q substituents in the fluoroquinolone coresand the respective X, R₈, R_(8′), and R₉ substituents on the7-substituted piperidino moieties introduced in the cores.

The compounds of the invention thus belong to a new generation ofdual-targeting, non-effluxed, diastereomeric, enantiomorphicantimicrobial 7-substituted piperidino-quinolone carboxylic acidderivatives. The compounds of the invention may be rightly called newgeneration triple-targeting, chiral, broad-spectrum antimicrobialagents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses certain compounds, dosage forms, andmethods of administering the compounds, to a human or other animalsubject. Specific compounds and compositions to be used in the inventionmust, accordingly, be pharmaceutically acceptable. As used herein, sucha “pharmaceutically-acceptable” compound is one that is suitable for usewith humans and/or animals without undue adverse side effects (such astoxicity, irritation, and allergic response) commensurate with areasonable benefit/risk ratio.

This invention describes fluoroquinolones of the formula I

wherein

-   -   R₁ is C₁₋₅ alkyl being unsubstituted or substituted with from 1        to 3 fluoro atoms, C₃₋₆ cycloalkyl being unsubstituted or        substituted with from 1 to 2 fluoro atoms, or aryl being        unsubstituted or substituted with from 1 to 3 fluoro atoms;    -   or when Q is CH and the nitrogen atom to which R₁ is linked        forms an optionally substituted 5-, 6- or 7-membered ring with        the carbon atom of Q, the ring optionally containing one or more        hetero atoms selected from nitrogen, oxygen or sulfur atoms,        said heteroatom(s) represented by T, preferably R₁ is CH₂CH₂—,        CH₂T—, CH₂CH₂CH₂—, CH₂CH₂T—, CH₂TCH₂—, TCH₂T—,        TCH₂CH₂CH₂CH₂—CH₂CH₂CH₂T—, CH₂TCH₂CH₂₋, or TCH₂CH₂T— where T        represents NH, O, or S. This 5- to 7-membered ring may be        substituted with 1 or 2 of the same substituents as those        defined above for R₁, preferably by one C₁-C₅ alkyl group.    -   Y is OR₃ where    -   R₃ is hydrogen;    -   R₃ is C₁-C₂₀ alkyl, such as straight chain or branched chain        aliphatic residues such as methyl, ethyl, propyl, isopropyl,        butyl, isobutyl, tertiary butyl, pentyl, hexyl or their branched        chain isomers;    -   R₃ is aralkyl such as benzyl, phenethyl, or phenylpropyl;    -   R₃ is CH₂CH(NH₂)COOH;    -   R₃ is (CH₂)_(n)—CHR₁₀—OCOR₁₁ or (CH₂)_(n)—CHR₁₀—OCO₂R₁₁ wherein        R₁₀ is H, or CH₃; n is 0-3 and R₁₁ is C₁-C₂₀ alkyl as        hereinbefore defined, or substituted C₁-C₆ alkyl with        substituents such as hydroxy, halogen, amino, or mercapto; or        aralkyl such as benzyl, phenethyl, phenylpropyl or    -   R₁₁ is    -   or R₃ is α-aminoalkanoyl such as α-aminopropionyl or R₃ is        alkanoylalkyl group such as acetoxymethyl, acetoxyethyl,        pivaloyloxy-methyl, or pivaloyloxyethyl group;    -   or R₃ is    -    wherein    -   A is CH or N, and when A is CH, Z is NH or NCH₃, and when A is        N, Z is CH, O, NH, S, or NCH₃; p is 0-2; q is 0-2, preferably it        is a group such as N-methylpiperidin-4-yl,        pyrrolidin-2-yl-ethyl, piperidin-2-yl-ethyl, or        morpholin-2-yl-ethyl; or    -   Y is NHR₂, wherein R₂ is H, C₁₋₂₀ alkyl such as straight chain        or branched chain aliphatic residues as defined above, C₃₋₆        cycloalkyl, substituted C₃₋₆ cycloalkyl wherein the substituent        is C₁₋₂ alkyl such as methyl or ethyl or trifluoroalkyl such as        trifluoromethyl or halogen such as fluorine, chlorine, bromine        or R₂ is aryl such as unsubstituted or substituted phenyl        wherein the substituent is C₁₋₃ alkyl, C₁₋₃ alkoxy, amino, or        halogen; heteroaryl such as pyridyl, pyrimidinyl, quinolinyl,        isoquinolinyl, faryl, oxazolinyl, thiazolyl, or thiadiazolyl,        all of which heteroaryl residues may be further substituted or        unsubstituted, wherein the substituent is methyl or ethyl;    -   or R₂ is an amino acid residue derived from one of the 20        naturally occurring amino acids viz. alanine, arginine,        asparagine, aspartic acid, cysteine, glutamine, glutamic acid,        glycine, histidine, isoleucine, leucine, lysine, methionine,        phenylalanine, proline, serine, threonine, tryptophan, tyrosine        and valine, or the optically active isomers thereof, or the        racemic mixtures thereof;    -   R₅ is H, C₁₋₅ alkyl, C₁₋₅ alkoxy, amino, C₁₋₅ alkylamino such as        —NHCH₃, N(CH₃)₂, and the like; or acylamino such as —NHCOCH₃,        —NHCOC(CH₃)₃, and the like;    -   Q is —N—, —C(R₈)— (R₈ being H, F, Cl, bromo, methoxy, C₁₋₄        alkyl, or unsubstituted or substituted C₁₋₄ alkoxy, wherein when        the alkoxy is substituted it is substituted by one or more        halogen atoms such as F, Cl, or Br), or when Q is CH and the        nitrogen atom to which R₁ is linked forms an optionally        substituted 5-, 6- or 7-membered ring with the carbon atom of Q;        the ring optionally containing one or more hetero atoms selected        from nitrogen, oxygen or sulfur atoms, said heteroatom(s)        represented by T, preferably R₁ is CH₂CH₂—, CH₂T—, CH₂CH₂CH₂—,        CH₂CH₂T—, CH₂TCH₂—, TCH₂T—, TCH₂CH₂CH₂CH₂—CH₂CH₂CH₂T—,        CH₂TCH₂CH₂₋, or TCH₂CH₂T— where T represents NH, O, or S. If the        ring is substituted, the substituent is as defined above for R₁.        This 5- to 7-membered ring may be substituted with 1 or 2 of the        same substituents as those defined above for R₁, preferably by        one C₁-C₅ alkyl group.    -   X is OR₄    -   wherein R₄ is hydrogen, C₁-C₂₀ alkyl as hereinbefore defined,        glycosyl, aralkyl such as benzyl; or C₁-C₆ alkanoyl such as        acetyl, propionyl, pivaloyl, stearoyl, or nonadecanoyl or        aminoalkanoyl such as aminoacetyl, aminopropionyl and the like        or an amino acid residue derived from one of the 20 naturally        occurring amino acids viz. alanine, arginine, asparagine,        aspartic acid, cysteine, glutamine, glutamic acid, glycine,        histidine, isoleucine, leucine, lysine, methionine,        phenylalanine, proline, serine, threonine, tryptophan, tyrosine        and valine, or the optically active isomers thereof, or the        racemic mixtures thereof; or R₄ is 1-aminocyclohexylcarbonyl or        COOR₁₁ wherein R₁₁ is as hereinbefore defined or R₄ is        —(CH₂)_(n)—CHR₁₀—OCOOR₁₁ where R₁₀ and R₁₁ are as hereinbefore        defined, or R₄ is C₆H₁₁O₆, PO₂(CH₃)H, PO₃H₂, PO₂(OCH₃)H or SO₃H        thus giving respectively the gluconic acid, phosphonic acid,        phosphoric acid and sulfonic acid ester derivatives of the        compounds;    -   or X is NR₆R₇,    -   wherein R₆ is H, C₁₋₂₀ alkyl as hereinbefore defined, C₃₋₆        cycloalkyl, aralkyl such as benzyl, phenethyl, or phenylpropyl;        C₁₋₂₀ alkanoyl such as COCH₃, COCH₂CH₃, or COC(CH₃)₃, or C₁₋₂₀        alkoxycarbonyl such as COOCH₃, COOCH₂CH₃, or COOC(CH₃)₃;        aralkyloxycarbonyl such as benzyloxycarbonyl, or        amino(C₁₋₂₀)alkanoyl such as aminoacetyl, aminopropionyl and the        like, or an amino acid residue derived from one of the 20        naturally occurring amino acids or the optically active isomers        thereof, or the racemic mixtures thereof. The amino acid residue        is derived from alanine, arginine, asparagine, aspartic acid,        cysteine, glutamine, glutamic acid, glycine, histidine,        isoleucine, leucine, lysine, methionine, phenylalanine, proline,        serine, threonine, tryptophan, tyrosine or valine. The amino        acid residue is derived from a single amino acid or from        combinations of amino acids that form dipeptide, tripeptide or        polypeptide amino acid unit residues wherein a terminal carboxy        group is optionally protected by C₁₋₄ alkyl or aralkyl groups        and a terminal amino group is optionally protected by a ^(t)-Boc        (teritarybutyloxycarbonyl), F-Moc (fluorenylmethoxycarbonyl) or        Cbz (benzyloxycarbonyl) group or R₆ may also be COOR₁₁ wherein        R₁₁ is as hereinbefore defined or R₆ is C₆H₁₁O₆ thus giving the        gluconic acid ester derivative of the compounds.

R₇ is H, C₁₋₆ alkyl as hereinbefore defined, C₃₋₆ cycloalkyl, aralkylsuch as benzyl, phenethyl, or phenylpropyl; C₁₋₆ alkanoyl such as COCH₃,COCH₂CH₃, COC(CH₃)₃, aralkyloxycarbonyl such as benzyloxycarbonyl oramino (C₁₋₂₀)alkanoyl such as aminoacetyl, aminopropionyl, etc.; or anamino acid residue derived from one of the 20 naturally occurring aminoacids or the optically active isomers thereof, or the racemic mixturesthereof. The amino acid residue is derived from alanine, arginine,asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine,histidine, isoleucine, leucine, lysine, methionine, phenylalanine,proline, serine, threonine, tryptophan, tyrosine or valine. The aminoacid residue is derived from a single amino acid or from combinations ofamino acids that form dipeptide, tripeptide or polypeptide amino acidunit residues, wherein a terminal carboxy group is optionally protectedby C₁₋₄ alkyl or aralkyl groups and a terminal amino group is optionallyprotected by a ^(t)-Boc (teritarybutyloxycarbonyl), F-Moc(fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl) group or

R₇ may be C₆H₁₁O₆ thus giving the gluconic acid ester derivative of thecompounds.

R₈/R₈′ are substituents at the 3/3-position of the piperidino ring andare the same or different and represent H, C₁₋₆ alkyl, substituted Ca₁₋₆alkyl wherein the substituent is amino, hydroxy, halogen such as one ormore fluorine, chlorine, or bromine atoms; alkylamino, or aralkyl suchas benzyl.

R₉ is a substituent at the 4-position or 5-position of the piperidinoring and represents H, C₁₋₆ alkyl, C₁₋₅ alkylamino, C₁₋₃ dialkylamino oraryl, aralkyl such as benzyl or phenethyl or a trihaloalkyl such astrifluoromethyl.

As used herein aryl is substituted or unsubstituted phenyl. The phenyl,alkyl, and cycloalkyl groups may be substituted at one or more positionsby the usual aromatic substituents such as halogen namely F, Cl, or Br;alkyl such as methyl, ethyl, trifluoromethyl, etc. Substituted phenylgroups include such as halophenyl, trifluoromethylphenyl,monofluorophenyl, 2-fluorophenyl, 4-fluorophenyl, or 2,4 difluorophenyl.

This invention also includes optical isomers, diastereomers,enantiomers, polymorphs, pseudopolymorphs, pharmaceutically acceptablesalts, hydrates, or biohydrolyzable esters, amides, imides, or solvatesof the fluoroquinolones of formula I and prodrugs of these compounds. Apseudopolymorph is a polymorph that differs from a true polymorph by theincorporation of solvent.

It has been found that the compounds of this invention, and compositioncontaining these compounds, are effective antimicrobial agents which area new generation of antibacterial agents, in particular a new generationof respiratory antibacterials, effective against multidrug-resistantpathogens with broad spectrum coverage of gram-positive andgram-negative microbes, such as sensitive and fluoroquinolone-resistantpneumococci, staphylococci, streptococci, anaerobes, enterococci andatypical pathogens. In addition, the compounds of the invention havepotent cidal action for fluoroquinolone-resistant strains. The compoundsof the invention have the preferred potential to address the unmet needfor orally effective drugs for the treatment of multi-drug-resistantpneumococcal infections like life-threatening pneumoniae and meningitis,to which pediatric and geriatric patients are vulnerable. They areunusually cidal for viridans streptococci, which are the causativegroups of strains responsible for bac-teremias, soft tissue infections,abscesses, sepsis and endocarditis. They are potential antitubercularagents against sensitive and resistant mycobacteria. The combination ofphysicochemical parameters contributed to the fluoroquinolone moleculesby the location, hydrogen-acceptor/-donor properties, spatial bulk,hydrophobicity, stereo-chemical orientation of the differentcontributing substituents at the respective positions surprisinglyprovide compounds of the invention that are not effluxed by efflux pumpbearing strains or have better uptake through bacterial cellularmembranes. The above described physicochemical parameters alsocontribute to their unusually favourable drugability properties. Theyare orally effective contribute to their unusually favourabledrugability properties. They are orally effective with once-a-daypotential. They have favourable penetration into tissues like the lung,liver, kidney and heart over serum thus enabling the targeting oforgan-specific infections. They are relatively non-phototoxic, withfavourable cytotoxicity and cardiotoxicity profiles which are usuallythe problem toxicities displayed by the fluoroquinolone class ofcompounds.

Among compounds that fall within the compounds of the aforementionedgeneral formula, optically active compounds and diastereomeric isomers,each having the substituent in a specific stereo and three-dimensionalspatial orientation have both excellent antibacterial activity and highsafety features.

The compounds of the invention are sufficiently basic to form acidaddition salts. The compounds are useful both in the free base form andthe form of acid addition salts, and both forms are within the purviewof the invention. The acid addition salts are in some cases a moreconvenient form for use. Examples of appropriate acid addition saltsinclude, but are not limited to acetate, benzenesulfonate, fumarate,hydrochloride, hydrobromide, hydroiodide, hydrogensulfate, isethionate,lactate, malate, maleate, malonate, methanesulfonate, pamoate(embonate), phosphate/diphosphate, stearate, succinate, sulfate,tartrate, trifluoroacetate, trifluoromethanesulfonate,p-toluenesulfonate, and the like. Preferred acid addition salts includehalides, sulfonates, carboxylates, phosphates, and the like. However,other appropriate pharmaceutically acceptable salts within the scope ofthe invention are those derived from other mineral acids, organic acidsand amino acids. The amino acid may be selected from one of the 20naturally occurring amino acids: alanine, arginine, asparagine, asparticacid, cysteine, glutamine, glutaric acid, glycine, histidine,isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,threonine, tryptophan, tyrosine or valine or the optically activeisomers thereof or the racemic mixtures thereof or dipeptides,tripeptides and polypeptides derived from the monoaminoacid unitsthereof. The compounds of the invention are also sufficiently acidic toform alkaline/base addition salts. Preferred alkali/base addition saltsinclude the alkali metal salts (such as sodium and potassium), alkalineearth metal salts (such as magnesium and calcium), inorganic salts, suchas, ammonium, substituted ammonium, choline and organic base salts frombasic amines such as diethanolamine, ethylenediamine, guanidine orheterocyclic amines such as piperidine, hydroxyethylpyrrolidine,hydroxyethylpiperidine, morpholine, piperazine, N-methyl piperazine andthe like or basic amino acids such as optically pure and racemic isomersof arginine, lysine, histidine, tryptophan and the like.

In practice, the use of the salt form inherently amounts to the use ofthe base form of the active. Acids used to prepare acid addition saltsinclude preferably those, which produce, when combined with the freebase, pharmaceutically acceptable salts. These salts have anions thatare relatively innocuous to the animal organism, such as a mammal, inpharmaceutical doses of the salts so that the beneficial propertyinherent in the free base are not vitiated by any side effectsascribable to the acid's anions.

The pharmaceutically acceptable acid addition salts of compounds of theformula I are prepared in a conventional manner by treating a solutionor suspension of the free base of formula I with about one chemicalequivalent of a pharmaceutically acceptable acid such as an inorganicacid or organic acid. Conventional concentration and recrystallizationtechniques are employed in isolating the salts.

For example, the free base can be dissolved in an aqueous alcoholsolution containing the appropriate acid and the salt is isolated byevaporation of the solution. Alternatively, they may be prepared byreacting the free base with an acid in an organic solvent so that thesalt separates directly. Where separation of the salt is difficult, itcan be precipitated with a second organic solvent, or can be obtained byconcentration of the solution.

Although pharmaceutically acceptable salts of the basic compounds arepreferred, all acid addition salts are within the scope of the presentinvention. All acid addition salts are useful as sources of the freebase form, even if the particular salt per se is desired only as anintermediate product. For example, when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a pharmaceutically acceptable salt by ionexchange procedures, these salts are clearly contemplated to be a partof this invention.

The amino moiety of piperidine is a potential point of formation for thesubject compounds of a pharmaceutically acceptable anionic salt; suchsalts are included in the subject invention compounds. Preferred saltsare acid addition salts with, for example, HCl, CH₃COOH, CH₃SO₃H, HCOOH,CF₃COOH, gluconic acid, C₁₋₂₀ straight chain or branched alkanoic acidsor one of the 20 naturally occurring amino acids as hereinbefore definedor dipeptide, tripeptide or polypeptide derivatives of the monoaminoacidunits thereof.

“Host” is a substrate capable of sustaining a microbe, preferably it isa living organism, and most preferably an animal, more preferably amammal, and more preferably still a human.

“Biohydrolyzable amides” are aminoacyl, acylamino, or other amides ofthe compounds of the invention, where the amide does not essentiallyinterfere, preferably does not interfere, with the activity of thecompound, or where the amide is readily converted in vivo by a host toyield an active compound.

“Biohydrolyzable imides” are imides of the compounds of the invention,where the imide does not essentially interfere, preferably does notinterfere, with the activity of the compound, or where the imide isreadily converted in vivo by a host to yield an active compound.Preferred imides are hydroxyimides.

“Biohydrolyzable esters” are esters of the compounds of the invention,where the ester does not essentially interfere, preferably does notinterfere, with the antimicrobial activity of the compound, or where theester is readily converted in a host to yield an active compound. Manysuch esters are known in the art. Such esters include lower alkylesters, lower acyloxy-alkyl esters (such as acetoxymethyl, acetoxyethyl,aminocarbonyloxymethyl, pivaloyloxylmethyl and pivaloyloxylethylesters); lactonyl esters (such as phthalidyl and thiophthalidyl esters)lower alkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl,ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters),alkoxyalkyl esters, choline esters and alkylacylaminoalkyl esters (suchas acetamidomethyl esters) and alkyl amino acid esters.

The illustration of specific protected forms and other derivatives ofthe formula I compounds are not intended to be limiting. The applicationof other useful protecting groups, salt forms, etc. is within theability of the skilled artisan.

“Optical isomer”, “stereoisomer”, “diastereomer” “polymorph”“pseudopolymorph”, “hydrates” and “solvates” as referred to herein havethe standard art recognized meanings. Solvates are generally formedduring the process of crystallization when molar or submolar amounts ofthe solvents get incorporated into the crystal structure of thecompound.

The compounds of the invention may contain chiral center(s), thus anysuch compound includes and contemplates each optical isomer,diastereomer or enantiomer thereof, in purified or substantiallypurified form, and mixtures thereof, including racemic mixtures.

The compounds of the invention may have one or more chiral centers. As aresult, one may selectively prepare one optical isomer, includingdiastereomer and enantiomer, over another, for example by use of chiralstarting materials, catalysts or solvents, one may prepare bothstereoisomers or both optical isomers, including diastereomers andenantiomers at once (a racemic mixture). Since the compounds of theinvention may exist as racemic mixtures, mixtures of optical isomers,including diastereomers and enantiomers, or stereoisomers, they may beseparated using known methods, such as chiral resolution, chiralchromatography and the like. In addition, it is recognized that oneoptical isomer, including diastereomer and enantiomer, or stereoisomermay have favorable properties over the other. Thus when disclosing andclaiming the invention, when one racemic mixture is disclosed, it isclearly contemplated that both optical isomers, including diastereomersand enantiomers, or stereoisomers substantially free of the other aredisclosed and claimed as well.

As used herein, a quinolone derivative includes prodrugs of a quinolone.

The preferred compounds of the invention are those compounds of FormulaI which are composed of on one hand the following core fluoroquinolonemoieties displayed below minus the respective 7-amino substituent:

It is preferred that one of the following amines can be combined withthe core fluoroquinolone moieties as shown above. The prefix “c”represents cyclo:

including their optical isomers and diastereomers.

The combinations of the above mentioned cores and the above mentionedamines provide the fluoroquinolone compounds of the invention.

The following exemplary compounds are made using the proceduresdescribed herein and variations thereof which are within the purview ofthe skilled artisan's practice. The examples below do not limit theinvention, but rather serve to illustrate some of embodiments of theinvention.

In the following tables (Tables 1-16), there are provided some examplesof the compounds of the invention. The lower case “c” represents“cyclo”.

TABLE 1

Q = C—H, C—(C₁-C₂) alkyl, C—OCH₃, C—F or N, and when Q is CH and thenitrogen atom to which R₁ is linked forms substituted 6 membered ringwith the carbon atom of Q and R₁ are C—CH₂CH₂C * H(CH₃) orC—OCH₂CH(CH₃); R₁ = C₂H₅, c-C₃H₅, or C₆H₃F₂(2,4), and when Q is CH andthe nitrogen atom to which R₁ is linked forms substituted 6 memberedring with the carbon atom of Q and R₁ are C—CH₂CH₂C * H(CH₃) orC—OCH₂CH(CH₃); R₅ = H, CH₃, or NH₂; R₈ = H, or CH₃; R₉ = H, or CH₃; andoptical isomers, pharmaceutically acceptable salts, hydrates,biohydrolyzable esters, polymorphs and pseudomorphs thereof. Q R₁ R₅ R₈R₉ Isomer C—H c-C₃H₅ H H H cis + trans C—H c-C₃H₅ H H H cis C—H c-C₃H₅ HH H trans C—H c-C₃H₅ H CH₃ H (±) C—H c-C₃H₅ H CH₃ H (+) C—H c-C₃H₅ H CH₃H (−) C—H c-C₃H₅ CH₃ H H trans C—H c-C₃H₅ CH₃ CH₃ H (±) C—H c-C₃H₅ CH₃CH₃ H (+) C—H c-C₃H₅ CH₃ CH₃ H (−) C—CH₃ C₂H₅ H H H cis ± trans C—CH₃C₂H₅ H H H cis C—CH₃ C₂H₅ H H H trans C—CH₃ C₂H₅ H CH₃ H (±) C—CH₃ C₂H₅H CH₃ H (+) C—CH₃ C₂H₅ H CH₃ H (−) C—CH₃ c-C₃H₅ H H H cis ± trans C—CH₃c-C₃H₅ H H H cis C—CH₃ c-C₃H₅ H H H trans C—CH₃ c-C₃H₅ H CH₃ H (±) C—CH₃c-C₃H₅ H CH₃ H (+) C—CH₃ c-C₃H₅ H CH₃ H (−) C—CH₃ c-C₃H₅ NH₂ H H cis ±trans C—CH₃ c-C₃H₅ NH₂ H H cis C—CH₃ c-C₃H₅ NH₂ H H trans C—CH₃ c-C₃H₅NH₂ CH₃ H (±) C—CH₃ c-C₃H₅ NH₂ CH₃ H (+) C—CH₃ c-C₃H₅ NH₂ CH₃ H (−)C—CH₃ C₆H₃F₂(2,4) H H H cis + trans C—CH₃ C₆H₃F₂(2,4) H H H cis C—CH₃C₆H₃F₂(2,4) H H H trans C—CH₃ C₆H₃F₂(2,4) H CH₃ H (±) C—CH₃ C₆H₃F₂(2,4)H CH₃ H (+) C—CH₃ C₆H₃F₂(2,4) H CH₃ H (−) C—C₂H₅ C₂H₅ H H H cis + transC—C₂H₅ C₂H₅ H H H cis C—C₂H₅ C₂H₅ H H H trans C—C₂H₅ C₂H₅ H CH₃ H (±)C—C₂H₅ C₂H₅ H CH₃ H (+) C—C₂H₅ C₂H₅ H CH₃ H (−) C—C₂H₅ c-C₃H₅ H H Hcis + trans C—C₂H₅ c-C₃H₅ H H H cis C—C₂H₅ c-C₃H₅ H H H trans C—C₂H₅c-C₃H₅ H CH₃ H (±) C—C₂H₅ c-C₃H₅ H CH₃ H (+) C—C₂H₅ c-C₃H₅ H CH₃ H (−)C—C₂H₅ C₆H₃F₂(2,4) H H H cis + trans C—C₂H₅ C₆H₃F₂(2,4) H H H cis C—C₂H₅C₆H₃F₂(2,4) H H H trans C—C₂H₅ C₆H₃F₂(2,4) H CH₃ H (±) C—C₂H₅C₆H₃F₂(2,4) H CH₃ H (+) C—C₂H₅ C₆H₃F₂(2,4) H CH₃ H (−) C—OCH₃ c-C₃H₅ H HCH₃ mixtures A ± B C—OCH₃ c-C₃H₅ H H CH₃ mixture A of isomers C—OCH₃c-C₃H₅ H H CH₃ mixture B of isomers C—OCH₃ c-C₃H₅ H CH₃ H (±) C—OCH₃c-C₃H₅ H CH₃ H (+) C—OCH₃ c-C₃H₅ H CH₃ H (−) C—OCH₃ c-C₃H₅ H CH₃ CH₃mixtures of isomers C—OCH₃ c-C₃H₅ NH₂ H CH₃ mixture A of isomers C—OCH₃c-C₃H₅ NH₂ H CH₃ mixture B of isomers C—OCH₃ c-C₃H₅ NH₂ H CH₃ mixturesA + B C—OCH₃ c-C₃H₅ NH₂ CH₃ H (±) C—OCH₃ c-C₃H₅ NH₂ CH₃ H (+) C—OCH₃c-C₃H₅ NH₂ CH₃ H (−) C—OCH₃ c-C₃H₅ NH₂ CH₃ CH₃ mixtures of isomersC—OCH₃ C₆H₃F₂(2,4) H CH₃ H (±) C—OCH₃ C₆H₃F₂(2,4) H CH₃ H (+) C—OCH₃C₆H₃F₂(2,4) H CH₃ H (−) C—OCH₃ C₆H₃F₂(2,4) NH₂ CH₃ H (±) C—OCH₃C₆H₃F₂(2,4) NH₂ CH₃ H (+) C—OCH₃ C₆H₃F₂(2,4) NH₂ CH₃ H (−) C—F c-C₃H₅ HCH₃ H (±) C—F c-C₃H₅ H CH₃ H (+) C—F c-C₃H₅ H CH₃ H (−) C—F c-C₃H₅ CH₃CH₃ H (±) C—F c-C₃H₅ CH₃ CH₃ H (+) C—F c-C₃H₅ CH₃ CH₃ H (−) C—F c-C₃H₅NH₂ H CH₃ mixtures A + B C—F c-C₃H₅ NH₂ H CH₃ mixture A of isomers C—Fc-C₃H₅ NH₂ H CH₃ mixture B of isomers C—F c-C₃H₅ NH₂ CH₃ H (±) C—Fc-C₃H₅ NH₂ CH₃ H (+) C—F c-C₃H₅ NH₂ CH₃ H (−) N c-C₃H₅ H H CH₃ mixturesA + B N c-C₃H₅ H H CH₃ mixture A of isomers N c-C₃H₅ H H CH₃ mixture Bof isomers N c-C₃H₅ H CH₃ H (±) N c-C₃H₅ H CH₃ H (+) N c-C₃H₅ H CH₃ H(−) N c-C₃H₅ CH₃ CH₃ H (±) N c-C₃H₅ CH₃ CH₃ H (+) N c-C₃H₅ CH₃ CH₃ H (−)N C₆H₃F₂(2,4) H H CH₃ mixtures A + B N C₆H₃F₂(2,4) H H CH₃ mixture A ofisomers N C₆H₃F₂(2,4) H H CH₃ mixture B of isomers N C₆H₃F₂(2,4) H CH₃ H(±) N C₆H₃F₂(2,4) H CH₃ H (+) N C₆H₃F₂(2,4) H CH₃ H (−) N C₆H₃F₂(2,4)CH₃ CH₃ H (±) N C₆H₃F₂(2,4) CH₃ CH₃ H (+) N C₆H₃F₂(2,4) CH₃ CH₃ H (−)C—CH₂CH₂C * H(CH₃) H H H cis ± trans C—CH₂CH₂C * H(CH₃) H H H cisC—CH₂CH₂C * H(CH₃) H H H trans C—CH₂CH₂C * H(CH₃) H H CH₃ mixtures A + BC—CH₂CH₂C * H(CH₃) H CH₃ H (±) C—CH₂CH₂C * H(CH₃) H CH₃ H (+)C—CH₂CH₂C * H(CH₃) H CH₃ H (−) C—OCH₂CH(CH₃) H H H cis + transC—OCH₂CH(CH₃) H H H cis C—OCH₂CH(CH₃) H H H trans C—OCH₂CH(CH₃) H H CH₃mixtures A + B C—OCH₂CH(CH₃) H CH₃ H (±) C—OCH₂CH(CH₃) H CH₃ H (+)C—OCH₂CH(CH₃) H CH₃ H (−)

TABLE 2

Q = C—H, C—CH₃, C—OCH₃, C—F or N, and when Q is CH and the nitrogen atomto which R₁ is linked forms substituted 6 membered ring with the carbonatom of Q and R₁ are C—CH₂CH₂C * H(CH₃) or C—OCH₂CH(CH₃); R₁ = C₂H₅,c-C₃H₅, or C₆H₃F₂(2,4), and when Q is CH and the nitrogen atom to whichR₁ is linked forms substituted 6 membered ring with the carbon atom of Qand R₁ are C—CH₂CH₂C * H(CH₃) or C—OCH₂CH(CH₃); R₅ = H, CH₃, or NH₂; R₈= H, or CH₃; R₉ = H, or CH₃; and optical isomers, pharmaceuticallyacceptable salts, hydrates, biohydrolyzable esters, polymorphs andpseudomorphs thereof. Q R₁ R₅ R₈ R₉ Isomers C—H c-C₃H₅ H H H cis ± transC—H c-C₃H₅ H H H cis C—H c-C₃H₅ H H H trans C—H c-C₃H₅ H CH₃ H (±) C—Hc-C₃H₅ H CH₃ H (+) C—H c-C₃H₅ H CH₃ H (−) C—H c-C₃H₅ CH₃ H H cis ± transC—H c-C₃H₅ CH₃ H H cis C—H c-C₃H₅ CH₃ H H trans C—H c-C₃H₅ CH₃ CH₃ H (±)C—H c-C₃H₅ CH₃ CH₃ H (+) C—H c-C₃H₅ CH₃ CH₃ H (−) C—CH₃ c-C₃H₅ H H Hcis + trans C—CH₃ c-C₃H₅ H H H cis C—CH₃ c-C₃H₅ H H H trans C—OCH₃ C₂H₅H H CH₃ mixture A of isomers C—OCH₃ C₂H₅ H H CH₃ mixture B of isomersC—OCH₃ c-C₃H₅ H H CH₃ mixture A ± B C—OCH₃ c-C₃H₅ H H CH₃ mixture A ofisomers C—OCH₃ c-C₃H₅ H H CH₃ mixture B of isomers C—OCH₃ c-C₃H₅ NH₂ HCH₃ mixture A ± B C—OCH₃ c-C₃H₅ NH₂ H CH₃ mixture A of isomers C—OCH₃c-C₃H₅ NH₂ H CH₃ mixture B of isomers C—F c-C₃H₅ NH₂ H CH₃ mixture A ± BC—F c-C₃H₅ NH₂ H CH₃ mixture A of isomers C—F c-C₃H₅ NH₂ H CH₃ mixture Bof isomers C—F c-C₃H₅ NH₂ CH₃ H (±) C—F c-C₃H₅ NH₂ CH₃ H (+) C—F c-C₃H₅NH₂ CH₃ H (−) N c-C₃H₅ H H H cis + trans N c-C₃H₅ H H H cis N c-C₃H₅ H HH trans N c-C₃H₅ H H CH₃ mixture A + B N c-C₃H₅ H H CH₃ mixture A ofisomers N c-C₃H₅ H H CH₃ mixture B of isomers N c-C₃H₅ H CH₃ H (±) Nc-C₃H₅ H CH₃ H (+) N c-C₃H₅ H CH₃ H (−) N C₆H₃F₂(2,4) H H H cis ± transN C₆H₃F₂(2,4) H H H cis N C₆H₃F₂(2,4) H H H Trans N C₆H₃F₂(2,4) H H CH₃Mixture A + B N C₆H₃F₂(2,4) H H CH₃ mixture A of isomers N C₆H₃F₂(2,4) HH CH₃ mixture B of isomers N C₆H₃F₂(2,4) H CH₃ H (±) N C₆H₃F₂(2,4) H CH₃H (+) N C₆H₃F₂(2,4) H CH₃ H (−) C—CH₂CH₂C * H(CH₃) H H H cis + transC—CH₂CH₂C * H(CH₃) H H H cis C—CH₂CH₂C * H(CH₃) H H H trans C—CH₂CH₂C *H(CH₃) H H CH₃ mixture A + B C—CH₂CH₂C * H(CH₃) H H CH₃ mixture A ofisomers C—CH₂CH₂C * H(CH₃) H H CH₃ mixture B of isomers C—CH₂CH₂C *H(CH₃) H CH₃ H (±) C—CH₂CH₂C * H(CH₃) H CH₃ H (+) C—CH₂CH₂C * H(CH₃) HCH₃ H (−) C—OCH₂CH(CH₃) H H H cis + trans C—OCH₂CH(CH₃) H H H cisC—OCH₂CH(CH₃) H H H trans C—OCH₂CH(CH₃) H H CH₃ mixture A + BC—OCH₂CH(CH₃) H H CH₃ mixture A of isomers C—OCH₂CH(CH₃) H H CH₃ mixtureB of isomers C—OCH₂CH(CH₃) H CH₃ H (±) C—OCH₂CH(CH₃) H CH₃ H (+)C—OCH₂CH(CH₃) H CH₃ H (−)

TABLE 3

Q = C—H, C—CH₃, C—OCH₃, C—F or N, and when Q is CH and the nitrogen atomto which R₁ is linked forms substituted 6 membered ring with the carbonatom of Q and R₁ are C—CH₂CH₂C * H(CH₃) or C—OCH₂CH(CH₃); R₁ = c-C₃H₅,or C₆H₃F₂(2,4), and when Q is CH and the nitrogen atom to which R₁ islinked forms substituted 6 membered ring with the carbon atom of Q andR₁ are C—CH₂CH₂C * H(CH₃) or C—OCH₂CH(CH₃); R₅ = H, CH₃, or NH₂; R₈ = H,or CH₃; R₉ = H, or CH₃; and optical isomers, pharmaceutically acceptablesalts, hydrates, biohydrolyzable esters, polymorphs and pseudomorphsthereof Q R₁ R₅ R₈ R₉ Isomers C—H c-C₃H₅ H CH₃ H (±) C—H c-C₃H₅ H CH₃ H(+) C—H c-C₃H₅ H CH₃ H (−) C—H c-C₃H₅ CH₃ CH₃ H (±) C—H c-C₃H₅ CH₃ CH₃ H(+) C—H c-C₃H₅ CH₃ CH₃ H (−) C—CH₃ c-C₃H₅ H CH₃ H (±) C—CH₃ c-C₃H₅ H CH₃H (+) C—CH₃ c-C₃H₅ H CH₃ H (−) C—OCH₃ c-C₃H₅ H H CH₃ mixture A ofisomers C—OCH₃ c-C₃H₅ H H CH₃ mixture B of isomers C—OCH₃ c-C₃H₅ NH₂ HCH₃ mixture A + B C—OCH₃ c-C₃H₅ NH₂ H CH₃ mixture A of isomers C—OCH₃c-C₃H₅ NH₂ H CH₃ mixture B of isomers C—F c-C₃H₅ NH₂ CH₃ H (±) C—Fc-C₃H₅ NH₂ CH₃ H (+) C—F c-C₃H₅ NH₂ CH₃ H (−) C—F c-C₃H₅ NH₂ H CH₃mixture A + B C—F c-C₃H₅ NH₂ H CH₃ mixture A of isomers C—F c-C₃H₅ NH₂ HCH₃ mixture B of isomers N c-C₃H₅ H H H cis + trans N c-C₃H₅ H H H cis Nc-C₃H₅ H H H trans N c-C₃H₅ H CH₃ H (±) N c-C₃H₅ H CH₃ H (+) N c-C₃H₅ HCH₃ H (−) N C₆H₃F₂(2,4) H H H cis + trans N C₆H₃F₂(2,4) H H H cis NC₆H₃F₂(2,4) H H H trans N C₆H₃F₂(2,4) H CH₃ H (±) N C₆H₃F₂(2,4) H CH₃ H(+) N C₆H₃F₂(2,4) H CH₃ H (−) C—CH₂CH₂C * H(CH₃) H CH₃ H (±) C—CH₂CH₂C *H(CH₃) H CH₃ H (+) C—CH₂CH₂C * H(CH₃) H CH₃ H (−) C—OCH₂CH(CH₃) H CH₃ H(±) C—OCH₂CH(CH₃) H CH₃ H (+) C—OCH₂CH(CH₃) H CH₃ H (−)

TABLE 4

Q = C—H, C—OCH₃, C—F or N, and when Q is CH and the nitrogen atom towhich R₁ is linked forms substituted 6 membered ring with the carbonatom of Q and R₁ are C—CH₂CH₂C * H(CH₃) or C—OCH₂CH(CH₃); R₁ = c-C₃H₅,or C₆H₃F₂(2,4), and when Q is CH and the nitrogen atom to which R₁ islinked forms substituted 6 membered ring with the carbon atom of Q andR₁ are C—CH₂CH₂C * H(CH₃) or C—OCH₂CH(CH₃); R₅ = H, CH₃, or NH₂; R₈ = H,or CH₃; R₉ = H, or CH₃; and optical isomers, pharmaceutically acceptablesalts, hydrates, biohydrolyzable esters, polymorphs and pseudomorphsthereof. Q R₁ R₅ R₈ R₉ Isomer C—H c-C₃H₅ H CH₃ H (±) C—H c-C₃H₅ H CH₃ H(+) C—H c-C₃H₅ H CH₃ H (−) C—H c-C₃H₅ CH₃ CH₃ H (±) C—H c-C₃H₅ CH₃ CH₃ H(+) C—H c-C₃H₅ CH₃ CH₃ H (−) C—OCH₃ c-C₃H₅ H H CH₃ mixture A + B C—OCH₃c-C₃H₅ H H CH₃ mixture A of isomers C—OCH₃ c-C₃H₅ H H CH₃ mixture B ofisomers C—OCH₃ c-C₃H₅ H H CH₃ mixture A + B C—OCH₃ c-C₃H₅ H H CH₃mixture A of isomers C—OCH₃ c-C₃H₅ H H CH₃ mixture B of isomers C—OCH₃c-C₃H₅ NH₂ H CH₃ mixture A + B C—OCH₃ c-C₃H₅ NH₂ H CH₃ mixture A ofisomers C—OCH₃ c-C₃H₅ NH₂ H CH₃ mixture B of isomers C—OCH₃ c-C₃H₅ NH₂ HCH₃ mixture A + B C—OCH₃ c-C₃H₅ NH₂ H CH₃ mixture A of isomers C—OCH₃c-C₃H₅ NH₂ H CH₃ mixture B of isomers C—OCH₃ c-C₃H₅ NH₂ CH₃ H (±) C—OCH₃c-C₃H₅ NH₂ CH₃ H (+) C—OCH₃ c-C₃H₅ NH₂ CH₃ H (−) C—F c-C₃H₅ NH₂ H CH₃mixture A + B C—F c-C₃H₅ NH₂ H CH₃ mixture A of isomers C—F c-C₃H₅ NH₂ HCH₃ mixture B of isomers C—F c-C₃H₅ NH₂ CH₃ H (±) C—F c-C₃H₅ NH₂ CH₃ H(+) C—F c-C₃H₅ NH₂ CH₃ H (−) N c-C₃H₅ H H H cis + trans N c-C₃H₅ H H Hcis N c-C₃H₅ H H H trans N c-C₃H₅ H CH₃ H (±) N c-C₃H₅ H CH₃ H (+) Nc-C₃H₅ H CH₃ H (−) N C₆H₃F₂(2,4) H H H cis + trans N C₆H₃F₂(2,4) H H Hcis N C₆H₃F₂(2,4) H H H trans N C₆H₃F₂(2,4) H CH₃ H (±) N C₆H₃F₂(2,4) HCH₃ H (+) N C₆H₃F₂(2,4) H CH₃ H (−) C—CH₂CH₂C * H(CH₃) H CH₃ H (±)C—CH₂CH₂C * H(CH₃) H CH₃ H (+) C—CH₂CH₂C * H(CH₃) H CH₃ H (−)C—OCH₂CH(CH₃) H CH₃ H (±) C—OCH₂CH(CH₃) H CH₃ H (+) C—OCH₂CH(CH₃) H CH₃H (−)

TABLE 5

Q = C—H, C—CH₃, C—OCH₃, C—F or N, and when Q is CH and the nitrogen atomto which R₁ is linked forms substituted 6 membered ring with the carbonatom of Q and R₁ are C—CH₂CH₂C * H(CH₃) or C—OCH₂CH(CH₃); R₁ = c-C₃H₅,or C₆H₃F₂(2,4), and when Q is CH and the nitrogen atom to which R₁ islinked forms substituted 6 membered ring with the carbon atom of Q andR₁ are C—CH₂CH₂C * H(CH₃) or C—OCH₂CH(CH₃); R₅ = H, CH₃, or NH₂, R₈ = H,or CH₃, R₉ = H, or CH₃, and optical isomers, pharmaceutically acceptablesalts, hydrates, biohydrolyzable esters, polymorphs and pseudomorphsthereof. Q R₁ R₅ R₈ R₉ Isomers C—H c-C₃H₅ H CH₃ H (±) C—H c-C₃H₅ H CH₃ H(+) C—H c-C₃H₅ H CH₃ H (−) C—H c-C₃H₅ CH₃ CH₃ H (±) C—H c-C₃H₅ CH₃ CH₃ H(+) C—H c-C₃H₅ CH₃ CH₃ H (−) C—CH₃ c-C₃H₅ H H H cis + trans C—CH₃ c-C₃H₅H H H cis C—CH₃ c-C₃H₅ H H H trans C—CH₃ c-C₃H₅ H CH₃ H (±) C—CH₃ c-C₃H₅H CH₃ H (+) C—CH₃ c-C₃H₅ H CH₃ H (−) C—OCH₃ c-C₃H₅ H H H cis + transC—OCH₃ c-C₃H₅ H H H cis C—OCH₃ c-C₃H₅ H H H trans C—OCH₃ c-C₃H₅ H H CH₃mixtures A + B C—OCH₃ c-C₃H₅ H H CH₃ mixture A of isomers C—OCH₃ c-C₃H₅H H CH₃ mixture B of isomers C—OCH₃ c-C₃H₅ H CH₃ H (±) C—OCH₃ c-C₃H₅ HCH₃ H (+) C—OCH₃ c-C₃H₅ H CH₃ H (−) C—OCH₃ c-C₃H₅ NH₂ H H cis + transC—OCH₃ c-C₃H₅ NH₂ H H cis C—OCH₃ c-C₃H₅ NH₂ H H trans C—OCH₃ c-C₃H₅ NH₂H CH₃ mixture A + B C—OCH₃ c-C₃H₅ NH₂ H CH₃ mixture A of isomers C—OCH₃c-C₃H₅ NH₂ H CH₃ mixture B of isomers C—OCH₃ c-C₃H₅ NH₂ CH₃ H (+) C—OCH₃c-C₃H₅ NH₂ CH₃ H (+) C—OCH₃ c-C₃H₅ NH₂ CH₃ H (−) C—F c-C₃H₅ CH₃ CH₃ H(±) C—F c-C₃H₅ CH₃ CH₃ H (+) C—F c-C₃H₅ CH₃ CH₃ H (−) C—F c-C₃H₅ NH₂ H Hcis + trans C—F c-C₃H₅ NH₂ H H cis C—F c-C₃H₅ NH₂ H H trans C—F c-C₃H₅NH₂ H CH₃ mixture A + B C—F c-C₃H₅ NH₂ H CH₃ mixture A of isomers C—Fc-C₃H₅ NH₂ H CH₃ mixture B of isomers C—F c-C₃H₅ NH₂ CH₃ H (±) C—Fc-C₃H₅ NH₂ CH₃ H (+) C—F c-C₃H₅ NH₂ CH₃ H (−) N c-C₃H₅ H H H cis + transN c-C₃H₅ H H H cis N c-C₃H₅ H H H trans N c-C₃H₅ H CH₃ H (±) N c-C₃H₅ HCH₃ H (+) N c-C₃H₅ H CH₃ H (−) N C₆H₃F₂(2,4) H H H cis + trans NC₆H₃F₂(2,4) H H H cis N C₆H₃F₂(2,4) H H H trans N C₆H₃F₂(2,4) H CH₃ H(±) N C₆H₃F₂(2,4) H CH₃ H (+) N C₆H₃F₂(2,4) H CH₃ H (−) C—CH₂CH₂C *H(CH₃) H CH₃ H (±) C—CH₂CH₂C * H(CH₃) H CH₃ H (+) C—CH₂CH₂C * H(CH₃) HCH₃ H (−) C—OCH₂CH(CH₃) H H H cis + trans C—OCH₂CH(CH₃) H H H cisC—OCH₂CH(CH₃) H H H trans C—OCH₂CH(CH₃) H CH₃ H (±) C—OCH₂CH(CH₃) H CH₃H (+) C—OCH₂CH(CH₃) H CH₃ H (−)

TABLE 6

Q = C—(C₁-C₂) alkyl, C—OCH₃, C—F or N; R₁ = C₂H₅, c-C₃H₅, orC₆H₃F₂(2,4); R₅ = H, or NH₂; R₈ = H, CH₃, or C₂H₅; R₉ = H, CH₃, or C₂H₅;and optical isomers, pharmaceutically acceptable salts, hydrates,biohydrolyzable esters, polymorphs and pseudomorphs thereof. Q R₁ R₅ R₈R₉ Isomers C—CH₃ C₂H₅ H H H cis + trans C—CH₃ C₆H₃F₂(2,4) H H H cis +trans C—C₂H₅ C₂H₅ H H H cis + trans C—C₂H₅ c-C₃H₅ H H H cis + transC—C₂H₅ C₆H₃F₂(2,4) H H H cis + trans C—OCH₃ c-C₃H₅ H H H cis + transC—OCH₃ c-C₃H₅ H H H Cis C—OCH₃ c-C₃H₅ H H H Trans C—OCH₃ c-C₃H₅ H H C₂H₅mixture A + B C—OCH₃ c-C₃H₅ H H C₂H₅ mixture A of isomers C—OCH₃ c-C₃H₅H H C₂H₅ mixture B of isomers C—OCH₃ c-C₃H₅ H CH₃ H (±) C—OCH₃ c-C₃H₅ HCH₃ H (+) C—OCH₃ c-C₃H₅ H CH₃ H (−) C—OCH₃ c-C₃H₅ H CH₃ CH₃ mixture ofisomers C—OCH₃ c-C₃H₅ H CH₃ C₂H₅ mixture of isomers C—OCH₃ c-C₃H₅ H CH₃C₂H₅ mixture of isomers C—OCH₃ c-C₃H₅ H C₂H₅ H (±) C—OCH₃ c-C₃H₅ H C₂H₅H (+) C—OCH₃ c-C₃H₅ H C₂H₅ H (−) C—OCH₃ c-C₃H₅ H CH₃ H (−) C—OCH₃ c-C₃H₅NH₂ H H cis + trans C—OCH₃ c-C₃H₅ NH₂ H H cis C—OCH₃ c-C₃H₅ NH₂ H HTrans C—OCH₃ c-C₃H₅ NH₂ H C₂H₅ mixture A + B C—OCH₃ c-C₃H₅ NH₂ H C₂H₅mixture A of isomers C—OCH₃ c-C₃H₅ NH₂ H C₂H₅ mixture B of isomersC—OCH₃ c-C₃H₅ NH₂ CH₃ H (±) C—OCH₃ c-C₃H₅ NH₂ CH₃ H (+) C—OCH₃ c-C₃H₅NH₂ CH₃ H (−) C—OCH₃ c-C₃H₅ NH₂ CH₃ CH₃ mixture of isomers C—OCH₃ c-C₃H₅NH₂ CH₃ C₂H₅ mixture of isomers C—OCH₃ c-C₃H₅ NH₂ C₂H₅ H (±) C—OCH₃c-C₃H₅ NH₂ C₂H₅ H (+) C—OCH₃ c-C₃H₅ NH₂ C₂H₅ H (−) C—F c-C₃H₅ NH₂ H Hcis + trans C—F c-C₃H₅ NH₂ H H cis C—F c-C₃H₅ NH₂ H H trans C—F c-C₃H₅NH₂ H C₂H₅ mixture A + B C—F c-C₃H₅ NH₂ H C₂H₅ mixture A of isomers C—Fc-C₃H₅ NH₂ H C₂H₅ mixture B of isomers C—F c-C₃H₅ NH₂ CH₃ H (±) C—Fc-C₃H₅ NH₂ CH₃ H (+) C—F c-C₃H₅ NH₂ CH₃ H (−) C—F c-C₃H₅ NH₂ CH₃ CH₃mixture of isomers C—F c-C₃H₅ NH₂ CH₃ C₂H₅ mixture of isomers C—F c-C₃H₅NH₂ C₂H₅ H (±) C—F c-C₃H₅ NH₂ C₂H₅ H (+) C—F c-C₃H₅ NH₂ C₂H₅ H (−) Nc-C₃H₅ H H H cis + trans N c-C₃H₅ H H H cis N c-C₃H₅ H H H trans NC₆H₃F₂(2,4) H H H cis + trans N C₆H₃F₂(2,4) H H H cis N C₆H₃F₂(2,4) H HH trans

TABLE 7

Q = C—OCH₃, or C—F, and when Q is CH and the nitrogen atom to which R₁is linked forms substituted 6 membered ring with the carbon atom of Qand R₁ is C—OCH₂CH(CH₃); R₁ = c-C₃H₅ and when Q is CH and the nitrogenatom to which R₁ is linked forms substituted 6 membered ring with thecarbon atom of Q and R₁ is C—OCH₂CH(CH₃); R₅ = H, or NH₂; R₈ = H, orCH₃; and optical isomers, pharmaceutically acceptable salts, hydrates,biohydrolyzable esters, polymorphs and pseudomorphs thereof. Q R₁ R₅ R₈Isomer C—OCH₃ c-C₃H₅ H H cis + trans C—OCH₃ c-C₃H₅ H H cis C—OCH₃ c-C₃H₅H H trans C—OCH₃ c-C₃H₅ H CH₃ (±) C—OCH₃ c-C₃H₅ H CH₃ (+) C—OCH₃ c-C₃H₅H CH₃ (−) C—OCH₃ c-C₃H₅ NH₂ H cis + trans C—OCH₃ c-C₃H₅ NH₂ H cis C—OCH₃c-C₃H₅ NH₂ H trans C—OCH₃ c-C₃H₅ NH₂ CH₃ (±) C—OCH₃ c-C₃H₅ NH₂ CH₃ (+)C—OCH₃ c-C₃H₅ NH₂ CH₃ (−) C—F c-C₃H₅ NH₂ H cis + trans C—F c-C₃H₅ NH₂ Hcis C—F c-C₃H₅ NH₂ H trans C—F c-C₃H₅ NH₂ CH₃ (±) C—F c-C₃H₅ NH₂ CH₃ (+)C—F c-C₃H₅ NH₂ CH₃ (−) C—OCH₂CH(CH₃) H H cis ± trans C—OCH₂CH(CH₃) H Hcis C—OCH₂CH(CH₃) H H Trans

TABLE 8

Q = C—OCH₃; R₁ = c-C₃H₅; R₅ = H, or NH₂; R₈ = H, or CH₃; and opticalisomers, pharmaceutically acceptable salts, hydrates, biohydrolyzableesters, polymorphs and pseudomorphs thereof. Q R₁ R₅ R₈ Isomer C—OCH₃c-C₃H₅ H H cis + trans C—OCH₃ c-C₃H₅ H H cis C—OCH₃ c-C₃H₅ H H transC—OCH₃ c-C₃H₅ H CH₃ (±) C—OCH₃ c-C₃H₅ H CH₃ (+) C—OCH₃ c-C₃H₅ H CH₃ (−)C—OCH₃ c-C₃H₅ NH₂ H cis + trans C—OCH₃ c-C₃H₅ NH₂ H cis C—OCH₃ c-C₃H₅NH₂ H trans C—OCH₃ c-C₃H₅ NH₂ CH₃ (±) C—OCH₃ c-C₃H₅ NH₂ CH₃ (+) C—OCH₃c-C₃H₅ NH₂ CH₃ (−)

TABLE 9

Q = C—OCH₃; R₁ = c-C₃H₅; R₅ = H, or NH₂; R₈ = H, or CH₃; and opticalisomers, pharmaceutically acceptable salts, hydrates, biohydrolyzableesters, polymorphs and pseudomorphs thereof. Q R₁ R₅ R₈ Isomer C—OCH₃c-C₃H₅ H H cis + trans C—OCH₃ c-C₃H₅ H H cis C—OCH₃ c-C₃H₅ H H transC—OCH₃ c-C₃H₅ H CH₃ (±) C—OCH₃ c-C₃H₅ H CH₃ (+) C—OCH₃ c-C₃H₅ H CH₃ (−)C—OCH₃ c-C₃H₅ NH₂ H cis + trans C—OCH₃ c-C₃H₅ NH₂ H cis C—OCH₃ c-C₃H₅NH₂ H trans C—OCH₃ c-C₃H₅ NH₂ CH₃ (±) C—OCH₃ c-C₃H₅ NH₂ CH₃ (+) C—OCH₃c-C₃H₅ NH₂ CH₃ (−)

TABLE 10

Q = C—OCH₃, or C—F; R₅ = H, or NH₂; R₆ = COCH₃, CO—(O—C₂-C₄ alkyl),COOCH₂C₆H₅, amino C₁₋₄ alkanoyl, carboxy amino C₁₋₄ alkanoyl,dipeptidoalkanoyl wherein the terminal amino group is unprotected orprotected with a ^(t)-Boc-protecting group. Q R₅ R₆ Isomer C-OCH₃ HCOCH₃ (±) C-OCH₃ H COOC₂H₅ (±) C-OCH₃ H COOC₂H₅ (+) C-OCH₃ H COOC₂H₅ (−)C-OCH₃ H COOC(CH₃)₃ (±) C-OCH₃ H COOC(CH₃)₃ (+) C-OCH₃ H COOC(CH₃)₃ (−)C-OCH₃ H COOCH₂C₆H₅ (±) C-OCH₃ H COOCH₂C₆H₅ (+) C-OCH₃ H COOCH₂C₆H₅ (−)C-OCH₃ H COC * H(CH₃)NH₂ mixture C-OCH₃ H COC * H(NH₂)CH(CH₃)₂ mixtureC-OCH₃ H COCH₂CH(NH₂)COOH mixture C-OCH₃ H COC * H(CH₃)NHCOC *H(CH₃)NH-^(t)-Boc mixture C-OCH₃ H COC * H(CH₃)NHCOC * H(CH₃)NH₂ mixtureC-F NH₂ COCH₃ mixture

TABLE 11

Y =NH₂, NHR₂, wherein R₂ is H, C₁₋₂ alkyl; or Y is OR₃ where R₃ is C₁₋₄alkyl (branched or unbranched); CH₂C₆H₅; C₂-C₃ carboxylic acid and theirC₁-C₄ alkyl esters (unbranched or branched); or five or six memberheterocycle (unsubstituted or substituted); or ∝-aminoalkanoyl such as∝-aminopropionyl; and optical isomers, pharmaceutically acceptablesalts, hydrates, biohydrolyzable esters, polymorphs and pseudomorphsthereof. Y Isomers NH₂ (±) NHCH₃ (±) NHC₂H₅ (±) NHCH(CH₃)COOH (±) OCH₃(±) OC₂H₅ (±) OC₃H₇(n) (±) OC₃H₇(i) (±) OC₄H₉(n) (±) OCH₂C₆H₅ (±)OCH₂COOH (±) OCH₂OCOCH₃ (±) OCH₂OCOCH(CH₃)₂ (±) OCH₂OCOC(CH₃)₃ (±)OCH₂CH₂OCOCH₃ (±) OCH₂CH₂OCOC(CH₃)₃ (±) O-(N-methyl-4-piperidinyl) (±)1-pyrrolidinyl (±) 1-piperidinyl (±) 1-piperazinyl (±) 1-morpholinyl (±)OCH₂CH(NH₂)COOH (±)

TABLE 12

Q = C—(C₁-C₂) alkyl, C—OCH₃, C-F or N, and when Q is CH and the nitrogenatom to which R₁ is linked forms substituted 6 membered ring with thecarbon atom of Q and R₁ is C—CH₂CH₂C * H(CH₃); R₁ = C₂H₅, c-C₃H₅, orC₆H₃F₂(2,4), and when Q is CH and the nitrogen atom to which R₁ islinked forms substituted 6 membered ring with the carbon atom of Q andR₁ is C—CH₂CH₂C * H(CH₃); R₅ = H, or NH₂; R₈ = H, C₃-C₄ alkyl(unbranched or branched), CH₂C₆H₅, or CF₃; and optical isomers,pharmaceutically acceptable salts, hydrates, biohydrolyzable esters,polymorphs and pseudomorphs thereof Q R₁ R₅ R₈ Isomers C—CH₃ C₂H₅ H H —C—CH₃ C₆H₃F₂(2,4) H H — C—C₂H₅ C₂H₅ H H — C—C₂H₅ c-C₃H₅ H H — C—C₂H₅C₆H₃F₂(2,4) H H — C—OCH₃ c-C₃H₅ H n-C₃H₇ cis + trans C—OCH₃ c-C₃H₅ Hi-C₃H₇ cis + trans C—OCH₃ c-C₃H₅ H n-C₄H₉ cis + trans C—OCH₃ c-C₃H₅ Hi-C₄H₉ cis + trans C—OCH₃ c-C₃H₅ H CH₂C₆H₅ cis + trans C—OCH₃ c-C₃H₅ HCF₃ cis + trans C—OCH₃ c-C₃H₅ NH₂ CF₃ cis + trans C—F c-C₃H₅ NH₂ CF₃cis + trans N C₆H₃F₂(2,4) H CF₃ cis + trans

TABLE 13

Q = C—H, C—(C₁-C₂) alkyl, C—OCH₃, C—F or N, and when Q is CH and thenitrogen atom to which R₁ is linked forms substituted 6 membered ringwith the carbon atom of Q and R₁ are C—CH₂CH₂C * H(CH₃) orC—OCH₂CH(CH₃); R₁ = C₂H₅, c-C₃H₅, or C₆H₃F₂(2,4), and when Q is CH andthe nitrogen atom to which R₁ is linked forms substituted 6 memberedring with the carbon atom of Q and R₁ are C—CH₂CH₂C * H(CH₃) orC—OCH₂CH(CH₃); R₅ = H, or NH₂; R₈ = H, CH₃, or C₂H₅; R₉ = H, CH₃, orC₂H₅; and optical isomers, pharmaceutically acceptable salts, hydrates,biohydrolyzable esters, polymorphs and pseudomorphs thereof. Q R₁ R₅ R₈R₉ Isomer C—H c-C₃H₅ H H H cis + trans C—H c-C₃H₅ H H H cis C—H c-C₃H₅ HH H trans C—H c-C₃H₅ H H CH₃ mixture C—H c-C₃H₅ H CH₃ H ± C—CH₃ C₂H₅ H HH cis + trans C—CH₃ C₂H₅ H H H cis C—CH₃ C₂H₅ H H H trans C—CH₃ C₂H₅ HCH₃ H cis + trans C—CH₃ c-C₃H₅ H H H cis + trans C—CH₃ c-C₃H₅ H H H cisC—CH₃ c-C₃H₅ H H H trans C—CH₃ c-C₃H₅ H CH₃ H cis + trans C—CH₃ c-C₃H₅NH₂ H H cis + trans C—CH₃ c-C₃H₅ NH₂ H H cis C—CH₃ c-C₃H₅ NH₂ H H transC—CH₃ C₆H₃F₂(2,4) H H H cis + trans C—CH₃ C₆H₃F₂(2,4) H H H cis C—CH₃C₆H₃F₂(2,4) H H H trans C—CH₃ C₆H₃F₂(2,4) H CH₃ H cis + trans C—C₂H₅C₂H₅ H H H cis + trans C—C₂H₅ C₂H₅ H H H cis C—C₂H₅ C₂H₅ H H H transC—C₂H₅ C₂H₅ H CH₃ H cis + trans C—C₂H₅ c-C₃H₅ H H H cis + trans C—C₂H₅c-C₃H₅ H H H cis C—C₂H₅ c-C₃H₅ H H H trans C—C₂H₅ c-C₃H₅ H CH₃ H ±C—C₂H₅ C₆H₃F₂(2,4) H H H cis + trans C—C₂H₅ C₆H₃F₂(2,4) H H H Cis C—C₂H₅C₆H₃F₂(2,4) H H H Trans C—C₂H₅ C₆H₃F₂(2,4) H CH₃ H ± C—OCH₃ c-C₃H₅ H H Hcis + trans C—OCH₃ c-C₃H₅ H H H Cis C—OCH₃ c-C₃H₅ H H H Trans C—OCH₃c-C₃H₅ H H CH₃ mixtures C—OCH₃ c-C₃H₅ H H CH₃ mixtures C—OCH₃ c-C₃H₅ H HCH₃ mixtures C—OCH₃ c-C₃H₅ H CH₃ H ± C—OCH₃ c-C₃H₅ H CH₃ CH₃ mixturesC—OCH₃ c-C₃H₅ H C₂H₅ H ± C—OCH₃ c-C₃H₅ H C₂H₅ CH₃ mixtures C—OCH₃ c-C₃H₅H C₂H₅ C₂H₅ mixtures C—OCH₃ c-C₃H₅ NH₂ H H cis + trans C—OCH₃ c-C₃H₅ NH₂H H cis C—OCH₃ c-C₃H₅ NH₂ H H trans C—OCH₃ c-C₃H₅ NH₂ H CH₃ mixturesC—OCH₃ c-C₃H₅ NH₂ CH₃ H ± C—OCH₃ c-C₃H₅ NH₂ CH₃ CH₃ mixtures C—OCH₃c-C₃H₅ NH₂ C₂H₅ H ± C—OCH₃ c-C₃H₅ NH₂ C₂H₅ CH₃ mixtures C—OCH₃ c-C₃H₅NH₂ C₂H₅ C₂H₅ mixtures C—F c-C₃H₅ H H CH₃ mixtures C—F c-C₃H₅ H H H ±C—F c-C₃H₅ H CH₃ H ± C—F c-C₃H₅ NH₂ H H cis + trans C—F c-C₃H₅ NH₂ H CH₃mixture C—F c-C₃H₅ NH₂ CH₃ H ± C—F c-C₃H₅ NH₂ C₂H₅ H ± N c-C₃H₅ H H Hcis + trans N c-C₃H₅ H H H cis N c-C₃H₅ H H H trans N c-C₃H₅ H H CH₃mixtures N c-C₃H₅ H CH₃ H N C₆H₃F₂(2,4) H H H cis + trans N C₆H₃F₂(2,4)H H H cis N C₆H₃F₂(2,4) H H H trans N C₆H₃F₂(2,4) H H CH₃ mixtures NC₆H₃F₂(2,4) H CH₃ H ± C—OCH₂CH(CH₃) H H H cis + trans C—OCH₂CH(CH₃) H HCH₃ mixtures C—OCH₂CH(CH₃) H CH₃ H ±

TABLE 14

Q = C-H, C-(C₁-C₂) alkyl, C—OCH₃, C—F or N, and when Q is CH and thenitrogen atom to which R₁ is linked forms substituted 6 membered ringwith the carbon atom of Q and R₁ is C—OCH₂CH(CH₃); R₁ = C₁₋₂ alkyl,c-C₃H₅, or C₆H₃F₂(2,4), and when Q is CH and the nitrogen atom to whichR₁ is linked forms substituted 6 membered ring with the carbon atom of Qand R₁ is C—OCH₂CH(CH₃); R₅ = H, or NH₂; R₉ = H, or C₂H₅; and opticalisomers, pharmaceutically acceptable salts, hydrates, biohydrolyzableesters, polymorphs and pseudomorphs thereof. Q R₁ R₅ R₉ Isomers C—H CH₃H H cis + trans C—CH₃ c-C₃H₅ H H cis + trans C—CH₃ c-C₃H₅ NH₂ H cis +trans C—CH₃ C₂H₅ H H cis + trans C—CH₃ C₆H₃F₂(2,4) H H cis + transC—C₂H₅ C₂H₅ H H cis + trans C—C₂H₅ c-C₃H₅ H H cis + trans C—C₂H₅C₆H₃F₂(2,4) H H cis + trans C—OCH₃ c-C₃H₅ H H cis + trans C—OCH₃ c-C₃H₅H C₂H₅ Mixture C—OCH₃ c-C₃H₅ NH₂ H cis + trans C—OCH₃ c-C₃H₅ NH₂ C₂H₅Mixture C—F c-C₃H₅ NH₂ H cis + trans N c-C₃H₅ H H cis + trans NC₆H₃F₂(2,4) H H cis + trans C—OCH₂CH(CH₃) H H cis + trans

TABLE 15

Q = C—H, C—OCH₃, C—F or N, and when Q is CH and the nitrogen atom towhich R₁ is linked forms substituted 6 membered ring with the carbonatom of Q and R₁ is C—OCH₂CH(CH₃); R₁ = c-C₃H₅, or C₆H₃F₂(2,4), and whenQ is CH and the nitrogen atom to which R₁ is linked forms substituted 6membered ring with the carbon atom of Q and R₁ is C—OCH₂CH(CH₃); R₅ = H,CH₃, or NH₂; and optical isomers, pharmaceutically acceptable salts,hydrates, biohydrolyzable esters, polymorphs and pseudomorphs thereof. QR₁ R₅ Isomers C—H c-C₃H₅ H cis + trans C—H c-C₃H₅ CH₃ cis + trans C—OCH₃c-C₃H₅ H cis + trans C—F c-C₃H₅ CH₃ cis + trans C—F c-C₃H₅ NH₂ cis +trans N c-C₃H₅ H cis + trans N C₆H₃F₂(2,4) H cis + trans C—OCH₂CH(CH₃) Hcis + trans

TABLE 16

Q = C—CH₃, or C—C₂H₅; R₁ = C₂H₅, c-C₃H₅, or C—C₆H₃F₂(2,4); andpharmaceutically acceptable salts, hydrates, biohydrolyzable esters,polymorphs and pseudomorphs thereof. Q R₁ C—CH₃ C₂H₅ C—CH₃ c-C₃H₅ C—CH₃C₆H₃F₂(2,4) C—C₂H₅ C₂H₅ C—C₂H₅ c-C₃H₅ C—C₂H₅ C₆H₃F₂(2,4)

Particularly preferred compounds of the invention are those where Q isC—OCH₃ and C—CH₃. A list of these preferred compounds are given belowunder the heading of specific compounds of the invention.

Specific Compounds of the Invention

-   1.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid (mixture of cis and trans isomers) and its salts;-   2.    trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3carboxylic    acid (racemic mixture of 4R,3R and 4S,3S) and its salts;-   3.    trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid (4R,3R) and its salts;-   4.    trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3carboxylic    acid (4S,3S) and its salts;-   5.    cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid (racemic mixture of 4S,3R and 4R,3S) and its salts;-   6.    cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid (4S,3R) and its salts;-   7.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid (mixture of cis and trans isomers) and its salts;-   8.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   9.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   10.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   11.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   12.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   13.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   14.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   15.    1-Ethyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   16.    1-(2,4-Difluorophenyl)-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   17.    (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid, its salts and its polymorphs;-   18.    (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs;-   19.    (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid methane sulfonate and its polymorphs;-   20.    (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid gluconate and its polymorphs;-   21.    (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid, its salts and its polymoprhs;-   22.    (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs;-   23.    (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid methane sulfonate and its polymorphs;-   24.    (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid gluconate and its polymorphs;-   25.    (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid, its salts and its polymorphs;-   26.    (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs;-   27.    (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid methane sulfonate and its polymorphs;-   28.    (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid gluconate and its polymorphs;-   29.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-acetylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   30.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-carbethoxyamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   31.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-^(t)-butyloxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   32.    (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-benzyloxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its salts;-   33.    (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-benzyloxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its salts;-   34.    (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-benzyloxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its salts;-   35.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   36.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   37.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   38.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   39.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid, its isomers, and its salts;-   40.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid, its isomers, and its salts;-   41.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid, its isomers, and its salts;-   42.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   43.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-diethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   44.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   45.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   46.    1-Ethyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   47.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   48.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   49.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   50.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3,5-trimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   51.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   52.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-3,5-diethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid, its isomers, and its salts;-   53.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid (mixture of cis and trans isomers) and its salts;-   54.    trans-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid (racemic mixture of 4R,3R and 4S,3S) and its salts;-   55.    trans-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid (4R,3R) and its salts;-   56.    trans-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid (4S,3S) and its salts;-   57.    cis-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid (racemic mixture of 4S,3R and 4R,3S) and its salts;-   58.    cis-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid (4S,3R) and its salts;-   59.    cis-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid (4R,3S) and its salts;-   60.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   61.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   62.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   63.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   64.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts,-   65.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   66.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3    carboxylic acid and its isomers and its salts;-   67.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   68.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   69.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-acetylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   70.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethoxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   71.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-t-butoxycarbonyl    amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid    and its isomers and its salts;-   72.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-benzyloxycarbonyl    amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid    and its isomers and its salts;-   73.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   74.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   75.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   76.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   77.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid, its isomers, and its salts;-   78.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid, its isomers, and its salts;-   79.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-methyl-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid, its isomers, and its salts;-   80.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-methyl-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   81.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3diethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   82.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   83.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   84.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   85.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   86.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   87.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3,5-trimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   88.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   89.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-3,5-diethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   90.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-1-piperidinyl)-4-oxo-quinoline3-carboxylic    acid and its salts;-   91.    1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   92.    cis/trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   93.    cis-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   94.    trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   95.    (±)-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   96.    cis/trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   97.    trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers, its salts and its polymorphs;-   98.    trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs;-   99.    cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   100.    cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs;-   101.    (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid, its salts and its polymorphs;-   102.    (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs;-   103.    (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid methane sulfonate and its polymorphs;-   104.    (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid gluconate and its polymorphs;-   105.    (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid, its salts and its polymorphs;-   106.    (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs;-   107.    (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid methane sulfonate and its polymorphs;-   108.    (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid gluconate and its polymorphs;-   109.    (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its salts;-   110.    (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs;-   111.    (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid methane sulfonate and its polymorphs;-   112.    (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid gluconate and its polymorphs;-   113.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-methylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   114.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-dimethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   115.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-ethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   116.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-dimethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   117.    1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-amino-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   118.    1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   119.    cis/trans-1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   120.    cis-1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   121.    trans-1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   122.    (±)-1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   123.    cis/trans-1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   124.    trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   125.    cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   126.    (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its salts;-   127.    (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its salts;-   128.    (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its salts;-   129.    trans-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   130.    cis-1-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   131.    (±)-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its salts;-   132.    (+)-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its salts;-   133.    (−)-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its salts;-   134.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   135.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   136.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   137.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   138.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-n-propyl-1-piperidinyl)-4-oxo-quinoline-3carboxylic    acid and its isomers and its salts;-   139.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-isopropyl    l-1-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers    and its salts;-   140.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-isobutyl    l-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers    and its salts;-   141.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-aminomethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   142.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-aminomethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   143.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   144.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   145.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   146.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   147.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,3,5-trimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   148.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,3,5-trimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   149.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-4-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and isomers and its salts;-   150.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-4-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   151.    1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-4-trifluoro    methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its    isomers and its salts;-   152.    5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-4-trifluoro    methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its    isomers and its salts;-   153.    1-Ethyl-6-fluoro-8-methyl-7-(4-amino-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   154.    1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   155.    cis/trans-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   156.    cis-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   157.    trans-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   158.    cis/trans-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   159.    cis-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   160.    trans-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   161.    (±)-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its salts;-   162.    (+)-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its salts;-   163.    (−)-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its salts;-   164.    (±)-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   165.    cis/trans-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   166.    cis/trans-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   167.    1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   168.    1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   169.    cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   170.    cis-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   171.    trans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   172.    cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   173.    cis-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   174.    trans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   175.    (±)-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its salts;-   176.    (+)-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its salts;-   177.    (−)-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its salts;-   178.    (+)-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   179.    cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   180.    cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3carboxylic    acid and its isomers and its salts;-   181.    1,8-Diethyl-6-fluoro-7-(4-amino-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   182.    1,8-Diethyl-6-fluoro-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   183.    cis/trans-1,8-Diethyl-6-fluoro-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   184.    cis-1,8-Diethyl-6-fluoro-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   185.    trans-1,8-Diethyl-6-fluoro-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   186.    cis/trans-1,8-Diethyl-6-fluoro-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   187.    cis-1,8-Diethyl-6-fluoro-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   188.    trans-1,8-Diethyl-6-fluoro-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   189.    (±)-1,8-Diethyl-6-fluoro-7-(4amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its salts;-   190.    (+)-1,8-Diethyl-6-fluoro-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its salts;-   191.    (−)-1,8-Diethyl-6-fluoro-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its salts;-   192.    (±)-1,8-Diethyl-6-fluoro-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   193.    cis/trans-1,8-Diethyl-6-fluoro-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   194.    cis/trans-1,8-Diethyl-6-fluoro-7-(4-amino-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   195.    1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   196.    1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   197.    cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   198.    cis-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   199.    trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   200.    cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   201.    cis-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   202.    trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   203.    (±)-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its salts;-   204.    (+)-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its salts;-   205.    (−)-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its salts;-   206.    (±)-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   207.    cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;-   208.    cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts;

Some preferred compounds of the invention are:

-   (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its polymorphs.-   (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs.-   (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid methane sulfonate and its polymorphs.-   (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid gluconate and its polymorphs.-   (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its polymorphs.-   (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs.-   (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid methane sulfonate and its polymorphs.-   (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid gluconate and its polymorphs.-   (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its polymorphs.-   (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs.-   (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid methane sulfonate and its polymorphs.-   (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid gluconate and its polymorphs.-   cis/trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts.-   cis-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts.-   trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts.-   cis/trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts.-   trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts.-   trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-7-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs.-   cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts.-   cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs.-   (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its polymorphs.-   (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs.-   (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid methane sulfonate and its polymorphs.-   (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid gluconate and its polymorphs.-   (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its polymorphs.-   (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs.-   (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid methane sulfonate and its polymorphs.-   (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid gluconate and its polymorphs.-   (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its polymorphs.-   (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride and its polymorphs.-   (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid methane sulfonate and its polymorphs.-   (−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid gluconate and its polymorphs.-   1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-dimethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid and its isomers and its salts.

Other preferred compounds of the invention include:

-   Crystalline polymorphic form of    (±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride—Polymorph A1:-   Crystalline polymorphic form of    (±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride—Polymorph A2:-   Crystalline polymorphic form of    (−)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride—Polymorph A1:-   Crystalline polymorphic form of    (−)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride—Polymorph A2:-   Crystalline polymorphic form of    (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride-Polymorph A1:-   Crystalline polymorphic form of    (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic    acid hydrochloride-Polymorph A2:

Another embodiment of the invention encompasses a process to make thecompounds of the invention, which comprises the following generalmethods.

General Methods

In general, the fluoroquinolone compounds were prepared by heating theappropriate 6,7-dihalo fluoroquinolone core moiety (bearing either afree 3 carboxylic acid or a 3 carboxylic acid ester or an O³O⁴ boranechelate) or the appropriate 8,9-dihalo fluoroquinolone core moiety(bearing an O-B-diacetoxy borane) with the appropriate,4-substituted/unsubstituted amino/hydroxy-3-substituted/unsubstitutedpiperidine moiety in an organic solvent, optionally in the presence of abase at 50°-120° C., preferably 50-90° C. for 4-72 hr preferably 16-24hr and isolating the product. Suitable solvents include acetone,alcohol, acetonitrile, dimethyl sulphoxide, N,N-dimethylformamide,preferably acetonitrile or dimethyl sulphoxide. Suitable bases includetriethylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,7-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably triethylamine. Whenthe amino function of the 7 piperidino substituent bears analkoxycarbonyl or aralkyloxycarbonyl as a protecting group, theprotecting group is removed by treatment with aqueous alkali orinorganic acid at 30-120° C., preferably 30-80° C. for 4-12 hours,preferably 4-6 hours and isolating the product.

Method 1

1-Cyclopropyl-6-fluoro-7-{(4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl)1-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and isomers were prepared by heating a mixture of1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid with appropriate {4-(amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl)}piperidinein an organic solvent optionally in the presence of a base at 50-120°C., preferably 90° C. for 4-72 hr. The solvent may be selected fromacetone, alcohol, acetonitrile, dimethyl sulphoxide,N,N-dimethylformamide preferably acetonitrile or dimethyl sulphoxide.The base may be selected from triethylamine, pyridine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or1,7-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably triethylamine.

Method 2

1-Cyclopropyl-6-fluoro-8-methoxy-7-{(4-amino/substitutedamino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl)-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and isomers were prepared by a procedure described in Method 1 byusing[1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O³,O⁴]difluoroboronchelate and appropriate {4-(amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl)}piperidine followed byhydrolysis of the obtained boron complex in presence of base such asaqueous sodium hydroxide, aqueous potassium hydroxide, triethylamine,diisopropylethylamine in solvents such as acetonitrile, methyl alcohol,ethyl alcohol.

Method 3

5-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-{(4-amino/substitutedamino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl)1-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and isomers were prepared by a procedure described in Method 1 byusing5-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and appropriate {4-(amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl)}piperidine.

Method 4

9-Fluoro-5-methyl-6,7-dihydro-8-(3/4/5-substituted-4-hydroxyl-1-piperidinyl)-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid its isomers were prepared by a procedure described in Method 1 byusing(O-B)-diacetoxy-{S-(−)-8,9-difluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxy}boraneand appropriate 3/4/5-substituted-4-hydroxy piperidine and optionallyhydrolyzing the obtained boron complex in the presence of a base.

Method 5

1-Cyclopropyl-6-fluoro-7-{(4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl)1-1-piperidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridone-3-carboxylicacid and isomers were prepared by a procedure described in Method 1 byusing1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridone-3-carboxylicacid and appropriate (4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl)}piperidine.

Method 6

1-(2,4-Difluorophenyl)-6-fluoro-7-{(4-amino/substitutedamino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl)1-1-piperidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridone-3-carboxylicacid and isomers were prepared by a procedure described in Method 1 byusingethyl-1-(difluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridone-3-carboxylateand appropriate {4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl}piperidine.

Method 7

1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-amino-3-alkyl/3,3dialkyl/3,5-dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and enantiomers were prepared by hydrolysis of racemic or opticallyactive1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-{4-benzyloxycarbonylamino/^(t)-butyloxycarbonylamino/ethoxycarbonylamino-3-alkyl/3,3-dialkyl/3,5-dialkyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid with aqueous alkali preferably aqueous sodium hydroxide orinorganic acid such as hydrochloric acid at ambient temperature for 2-12hr.

Method 8

1-Cyclopropyl-6-fluoro-8-methyl-7-(4-amino/substitutedamino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and isomers were prepared by a procedure described in Method 1 byusing[1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O³,O⁴]difluoroboronchelate and appropriate {4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl}piperidine and optionally hydrolyzingthe obtained boron complex in the presence of a base.

Method 9

1-Cyclopropyl-6-fluoro-8-ethyl-7-{4-amino/substitutedamino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and isomers were prepared by a procedure described in Method 1 byusing[1-cyclopropyl-6,7-difluoro-8-ethyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O³,O⁴]difluoroboronchelate and appropriate {4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl}piperidine and optionally hydrolyzingthe obtained boron complex in the presence of a base.

Method 10

5-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-(4-amino/substitutedamino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and isomers were prepared by a procedure described in Method 1 byusing[5-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O³,O⁴]difluoroboronchelate and appropriate {4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl}piperidine and optionally hydrolyzingthe obtained boron complex in the presence of a base.

Method 11

1-Ethyl-6-fluoro-8-methyl-7-(4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and isomers were prepared by a procedure described in Method 1 byusing[1-ethyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O³,O⁴]difluoroboronchelate and appropriate {4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl}piperidine and optionally hydrolyzingthe obtained boron complex in the presence of a base.

Method 12

1,8-Diethyl-6-fluoro-7-{4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and isomers were prepared by a procedure described in Method 1 byusing[1,8-diethyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O³,O⁴]difluoroboronchelate and appropriate {4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl}piperidine and optionally hydrolyzingthe obtained boron complex in the presence of a base.

Method 13

1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-{4-amino/substitutedamino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and isomers were prepared by a procedure described in Method 1 byusing[1-(2,4-Difluorophenyl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O3,O4]difluoroboronchelate and appropriate {4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl}piperidine and optionally hydrolyzingthe obtained boron complex in the presence of a base.

Method 14

1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-{4-amino/substitutedamino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and isomers were prepared by a procedure described in Method 1 byusing[1-(2,4-Difluorophenyl)-6,7-difluoro-8-ethyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O3,O4]difluoroboronchelate and appropriate {4-amino/substituted amino/disubstitutedamino/hydroxy-3-alkyl/3,3-dialkyl}piperidine and optionally hydrolyzingthe obtained boron complex in the presence of a base.

Another aspect of the invention are novel amines that can be used toprepare the compounds of formula 1. The amines are listed below and themethods for their preparation are included in parenthesis alongside eachone of them as follows:

-   4-Amino-3,3-dimethylpiperidine (prepared as in Preparation 10,    step 2) and optical enantiomers thereof (prepared as in Preparation    37 and Preparation 38);-   4-Methylamino-3,3-dimethylpiperidine (prepared as in Preparation 11)    and optical enantiomers thereof (can be prepared by methods known to    those skilled in the art);-   4-Ethylamino-3,3-dimethylpiperidine (prepared as in Preparation 12)    and optical enantiomers thereof (can be prepared by methods known to    those skilled in the art);-   4-Cyclopropylamino-3,3-dimethylpiperidine (prepared as in    Preparation 13) and optical enantiomers thereof (can be prepared by    methods known to those skilled in the art);-   4-Dimethylamino-3,3-dimethylpiperidine (prepared as in    Preparation 14) and optical enantiomers thereof (can be prepared by    methods known to those skilled in the art);-   4-Benzylamino-3,3-dimethylpiperidine and optical enantiomers thereof    (can be prepared by methods known to those skilled in the art);-   4-Acetylamino-3,3-dimethylpiperidine (prepared as in Preparation 16)    and optical enantiomers thereof (can be prepared by methods known to    those skilled in the art);-   4-Carbethoxyamino-3,3-dimethylpiperidine (prepared as in    Preparation 15) and optical enantiomers thereof (can be prepared by    methods known to those skilled in the art);-   (±)-4-^(t)-Butyloxycarbonylamino-3,3-dimethylpiperidine (can be    prepared according to Preparation 19, step 7 using the racemic    mixture of isomers in place of the optical enantiomer);-   (+)-4-^(t)-Butyloxycarbonylamino-3,3-dimethylpiperidine (prepared    according to Preparation 19, step 7);-   (−)-4-^(t)-Butyloxycarbonylamino-3,3-dimethylpiperidine (prepared    according to Preparation 19, step 7);-   4-Benzyloxycarbonylamino-3,3-dimethylpiperidine (prepared as in    Preparation 18) and optical enantiomers thereof (can be prepared by    methods known to those skilled in the art);-   4-Amino-1-benzyl-3,3-dimethylpiperidine (prepared as in Preparation    10, step 2)and optical enantiomers thereof (can be prepared by    methods known to those skilled in the art);-   4-Amino-1-carbethoxy-3,3-dimethylpiperidine and optical enantiomers    thereof (can be prepared by methods known to those skilled in the    art);-   4-Amino-1-^(t-)butyloxycarbonyl-3,3-dimethylpiperidine (prepared as    in Preparation 18, step 2) and optical enantiomers thereof (can be    prepared by methods known to those skilled in the art);-   (±)-4-Amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine (prepared as    in Preparation 19, step 2);-   (+)-4-Amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine (prepared as    in Preparation 19, step 3); and-   (−)-4-Amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine (prepared as    in Preparation 19, step 4);-   4-Amino-1-carbethoxy-3-methylpiperidine (prepared as in Preparation    1, step 1);-   4-Amino-3,5-diethyl-3-methylpiperidine (prepared as in Preparation    32);-   4-Amino-1-carbethoxy-3,5-dimethylpiperidine (prepared as in    Preparation 25, step 2);-   4-Amino-1-benzyl-3,5-diethyl-3-methylpiperidine (prepared as in    Preparation 32);-   4-Amino-3,5-dimethyl-3-ethylpiperidine (prepared as in Preparation    33);-   4-Amino-1-benzyl-3,5-dimethyl-3-ethylpiperidine (prepared as in    Preparation 33);-   4-Amino-3,5-diethylpiperidine (prepared as in Preparation 30);-   4-Amino-1-benzyl-3,5-diethylpiperidine (prepared as in Preparation    30);-   4-Amino-3,3,5-trimethylpiperidine (prepared as in Preparation 31);-   4-Amino-3,3-diethylpiperidine (prepared as in Preparation 24);-   4-Amino-1-benzyl-3,3-diethylpiperidine (prepared as in Preparation    24);-   4-Amino-3,5-dimethylpiperidine (prepared as in Preparation 25);-   Mixture of isomers of 4-amino-1-carbethoxy-3,5-dimethylpiperidine    (prepared as in Preparation 25, step 1);-   4-Amino-3-ethyl-3-methylpiperidine (prepared as in Preparation 20);-   4-Amino-1-benzyl-3-ethyl-3-methylpiperidine (prepared as in    Preparation 20);-   4-Acetylamino-1-benzyl-3,3-dimethyl piperidine (prepared as in    Preparation 16);-   cis or trans-4-t-Butyloxycarbonylamino-1-benzyl-3-methylpiperidine    (prepared as in Preparation 34, step 4);-   cis-4-t-Butyloxycarbonylamino-3-methylpiperidine (prepared as in    Preparation 35);-   trans-4-t-Butyloxycarbonylamino-3-methylpiperidine (prepared as in    Preparation 36);-   1-Benzyl-4-carbethoxyamino-3,3-dimethyl piperidine (prepared as in    Preparation 15);-   1-Benzyl-4-cyclopropylamino-3-ethyl-3-methylpiperidine (prepared as    in Preparation 22);-   1-Benzyl-4-methylamino-3-ethyl-3-methylpiperidine (prepared as in    Preparation 21);-   1-Benzyl-4-dimethylamino-3-ethyl-3-methylpiperidine (prepared as in    Preparation 23);-   1-Carbethoxy-4-ethylamino-3-methylpiperidine (prepared as in    Preparation 3, step 1);-   4-Cyclopropylamino-3-methylpiperidine (prepared as in Preparation 4,    step 2);-   1-Carbethoxy-4-cyclopropylamino-3-methylpiperidine (prepared as in    Preparation 4, step 2);-   1-Carbethoxy-4-dimethylamino-3-methylpiperidine (prepared as in    Preparation 5, step 1);-   4-Cyclopropylamino-3-ethylpiperidine (prepared as in Preparation 8);-   4-Cyclopropylamino-3-ethyl-3-methylpiperidine (prepared as in    Preparation 22);-   4-Cyclopropylamino-3,5-dimethylpiperidine (prepared as in    Preparation 28);-   4-Dimethylamino-3-ethylpiperidine (prepared as in Preparation 9);-   4-Dimethylamino-3-methylpiperidine (prepared as in Preparation 5,    step 2);-   4-Dimethylamino-3,5-dimethylpiperidine (prepared as in Preparation    29);-   4-Dimethylamino-3-ethyl-3-Methylpiperidine (prepared as in    Preparation 23);-   4-Methylamino-3-methylpiperidine (prepared as in Preparation 2, step    2);-   4-Ethylamino-3-methylpiperidine (prepared as in Preparation 3, step    2);-   4-Methylamino-3-ethylpiperidine (prepared as in Preparation 7);-   4-Methylamino-3-ethyl-3-methylpiperidine (prepared as in Preparation    21);-   4-Methylamino-3,5-dimethylpiperidine (prepared as in Preparation    26);-   4-Ethylamino-3,5-dimethylpiperidine (prepared as in Preparation 27);

In addition, the invention also provides novel intermediate amines thatcan be used to prepare the amines listed above. The novel intermediateamines are listed below and the methods for their preparation areincluded in parenthesis alongside each one of them as follows:

-   3,3-Dimethyl-4-piperidone (prepared as in Preparation 17);-   ^(t)-Butyloxycarbonyl-3,3-dimethyl-4-piperidone (prepared as in    Preparation 18, step 1);-   1-Benzyloxycarbonyl-3,3-dimethyl-4-piperidone (prepared as in    Preparation 19, step 1);-   (±)-4-Benzyloxycarbonylamino-1-^(t-)butyloxycarbonyl-3,3-dimethylpiperidine    (prepared as in Preparation 18, step 3);-   (+)-1-Benzyloxycarbonyl-4-^(t-)butyloxycarbonylamino-3,3-dimethylpiperidine    prepared as in Preparation 19, step 5);-   (−)-1-Benzyloxycarbonyl-4-^(t-)butyloxycarbonylamino-3,3-dimethylpiperidine    (prepared as in Preparation 19, step 6);-   1-Carbethoxy-3,5-dimethyl-4-piperidone (prepared as in Preparation    25, step 1);-   3,3,5-Trimethyl-4-piperidone (prepared as in Preparation 31);-   Ethyl-1-benzyl-3-methyl-4-oxo-piperidine-3-carboxylate (prepared as    in Preparation 34, step 1);

The above mentioned novel intermediates are used to prepare the novelamines of the invention. The intermediates can be classified as (a) theunprotected dialkyl or trialkyl 4-piperidones, (b) the dialkyl ortrialkyl 1-N protected 4-piperidones and (c) the dialkyl 1-N protected,4-protected amino piperidines.

The unprotected dialkyl or trialkyl 4-piperidone intermediates can beused to prepare the corresponding amines by using the known art oftransforming a carbonyl functionality to an amine functionality by usingreagents such as ammonium acetate, methyl amine hydrocholide, ethylamine hydrochloride, cyclopropyl amine etc to form an iminofunctionality which upon subsequent reduction can produce desired amineafter reduction. The reducing agents can be selected from sodium cyanoborohydride or palladium on carbon in a solvent such as methanol,ethanol, ethyl acetate etc.

The dialkyl or trialkyl 1-N protected 4-piperidones are used to preparethe corresponding deprotected amines by using the known art ofdeprotection such as hydrogenolysis to deprotect a benzyloxycarbonylmoiety or a benzyl moiety by stirring the intermediate in the presenceof catalysts and a hydrogen source. The catalyst can be selected frompalladium on carbon, palladium hydroxide on carbon and hydrogen sourcecan be selected from hydrogen gas or ammonium formate, cyclohexene, insolvents such as methanol ethanol, ethyl acetate etc.

The dialkyl 1-N protected, 4-protected amino piperidines can be used toprepare the corresponding deprotected amines by using the known art ofdeprotection as described in the previous paragraph to remove abenzyloxycarbonyl or a benzyl moiety and the known art of removing abutyloxycarbonyl group by stirring the intermediate, in the presence ofinorganic acids such as concentrated hydrochloric acid or organic acidssuch as trifluoro acetic acid in solvents such as tetrahydrofuran,dioxane etc.

The preparations 1-38 include examples of the specific preparativemethods used of how to use the described amine intermediates for thepreparation of the corresponding novel amines of the invention.

The pharmaceutically acceptable acid addition salts of compounds of theformula I are prepared in a conventional manner by treating a solutionor suspension of the free base of the formula I with about one chemicalequivalent of a pharmaceutically acceptable acid such as an inorganicacid or organic acid. Conventional concentration and recrystallizationtechniques are employed in isolating the salts. For example, the freebase can be dissolved in an aqueous alcohol solution containing theappropriate acid and the salt is isolated by evaporation of thesolution. Alternatively, they may be prepared by reacting the free basewith an acid in an organic solvent so that the salt separates directly.Where separation of the salt is difficult, it can be precipitated with asecond organic solvent, or can be obtained by concentration of thesolution. Examples of appropriate acid addition salts include, but arenot limited to acetate, benzenesulfonate, fumarate, hydrochloride,hydrobromide, hydroiodide, hydrogensulfate, isethionate, lactate,malate, maleate, malonate, methanesulfonate, pamoate (embonate),phosphate/diphosphate, stearate, succinate, sulfate, tartrate,trifluoroacetate, trifluoromethanesulfonate, p-toluenesulfonate, and thelike. Preferred acid addition salts include halides, sulfonates,carboxylates, phosphates, and the like. However, other appropriatepharmaceutically acceptable salts within the scope of the invention arethose derived from other mineral acids, organic acids and amino acids.The amino acid may be selected from one of the 20 naturally occurringamino acids: alanine, arginine, asparagine, aspartic acid, cysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine or valine or the optically active isomers thereofor the racemic mixtures thereof or dipeptides, tripeptides andpolypeptides derived from the monoaminoacid units thereof.

The pharmaceutically acceptable alkali/base addition salts of compoundsof formula I may be prepared by conventional methods from thecorresponding acids e.g. by reaction with about one equimolar amount ofan alkali/base. Preferred alkali/base addition salts include the alkalimetal salts (such as sodium and potassium), alkaline earth metal salts(such as magnesium and calcium), inorganic salts, such as ammonium,substituted ammonium, choline and organic base salts from basic aminessuch as diethanolamine, N-methyl glucamine, ethylenediamine, guanidineor heterocyclic amines such as piperidine, hydroxyethylpyrrolidine,hydroxyethylpiperidine, morpholine, piperazine, N-methyl piperazine andthe like or basic amino acids such as optically pure and racemic isomersof arginine, lysine, histidine, tryptophan and the like.

The hydrates, pseudopolymorphs, polymorphs and solvates of all thecompounds of the invention are also included and are prepared byconventional methods.

The present invention also encompasses the process of making theintermediate amines, as illustrated in the detailed preparations thatare used in the condensation with the fluoroquinolone nucleus. Forinstance, the 3-substituted-4-aminopiperidine intermediates can exist asa mixture of cis and trans isomers and the mixture was prepared by theprocedure described in Preparation 1. The mixture of cis and transisomers of 4-amino-3-methylpiperidine was prepared by a sequence asdescribed in Preparation 34. Each cis and trans isomer is a racemicmixture and can be resolved into optically active enantiomeric forms bythe usual methods of optical resolution of amines known to those skilledin the art. Other 3-substituted-4-aminopiperidines were synthesisedusing a similar method.

The 4-amino-3,5-dimethylpiperidine intermediate was obtained in thefollowing manner. 4Amino-1-carbethoxy-3,5-dimethylpiperidine (a mixtureof isomers) was prepared according to the procedure described inPreparation 25 and separated by silica gel column chromatography intothe two major mixtures of isomers, one mixture designated as uppermixture A and the other designated as lower mixture B of isomers.Conformations of these mixtures of isomers were not assigned. Using anyone of the mixtures of isomers of 4-amino-3,5-dimethylpiperidine, somecompounds of the invention can be prepared by condensing the respectivemixture of isomers of 4-amino-3,5-dimethyl-piperidine with[1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylate-O³,O⁴]difluoroboronchelate, as exemplified in the section on examples described later inthis specification.

The present invention also encompasses an antiinfective composition forthe treatment of humans and animals in need of prophylaxix and/ortherapy for systemic or topical infections especially resistantgram-positive organism infections, gram-negative organism infections,mycobacterial infections and nosocomial pathogen infections, whichcomposition comprises an amount of a compound of the invention, thederivatives, isomers, salts, polymorphs, pseudopolymorphs, and hydratesthereof, substantially sufficient to eradicate said infection, but notto cause any undue side effects. Compounds and compositions of thisinvention can be administered to humans and animals who are at risk ofbeing infected, for example a compound or composition of this inventioncan be administered to a patient prior to and/or after surgery.

In addition the compounds of the invention have superior bactericidalactivity against pneumococci and streptococci of various groups. Cidalfeatures available in such molecules add to their clinicalattractiveness as it would offer clinicians a valuable treatment optionto treat a broader range of infections caused by staphylococci, MRSA,MRSE, pneumococci, streptococci, mycobacteria and diverse range ofanaerobic bacteria of clinical importance in a situation such aspatients allergic to β-lactam or possibility of infections due tomacrolide resistant strains of streptococci and pneumococci orMRSA/QRSA. For anaerobic bacterial infections, currently availabletreatment options are rather limited due to reasons such as inadequatepotency or gaps in the spectrum of anaerobic pathogens covered. Such isthe case with macrolides. With β-lactam antibacterials, the majorshortcoming is their liability to a variety of β-lactamases, the druginactivating enzymes elaborated by commonly encountered anaerobicpathogens. Older fluoroquinolones such as ciprofloxacin, levofloxacin,pefloxacin also suffered due to inadequate anti-anaerobic potency. Themolecules of invention demonstrate several distinct gains inantimicrobial properties against anaerobic pathogens vis-à-vis earlierantibacterial agents of the β-lactam, macrolide and fluoroquinoloneclasses.

It has been found that the compounds of this invention, and compositionscontaining these compounds, are effective antimicrobial agents against abroad range of pathogenic microorganisms with advantages in lowsusceptibility to microbial resistance, reduced toxicity, and improvedpharmacology.

Moreover, the molecules of the invention, chiral compounds, salts,polymorphs, pseudopolymorphs and hydrates thereof, also retain the othervaluable features, of being bactericidal to fluoroquinolone resistantstaphylococci (QRSA with resistant gyrase) and even to staphylococcaland pneumococcal isolates possessing Nor A efflux pumps and other effluxpumps. The compounds of the invention also display efflux pumpinhibitory activity. A combination of all these properties coupled withoverall good safety and tolerability observed in a new molecule rendersthem worthy of therapeutic use in humans and animals. By virtue of suchfeatures, they have considerable advantages over existingfluoroquinolone antibacterials, in particular in the treatment ofrespiratory diseases and infections of skin and soft tissue.

The above list of pathogens is merely by way of example and is in no wayto be interpreted as limiting. Streptococci are implicated as one of themost common pathogens, in both the pediatric and adult population indiverse infections/diseases. Examples which may be mentioned ofdiseases, which can thus be prevented, alleviated and/or cured by theformulations according to the invention include but are not limited toare meningitis, otitis externa, otitis media; pharyngitis; pneumonia;life-threatening bacteremia, peritonitis; pyelonephritis; cystitis;endocarditis; systemic infections; bronchitis; arthritis; localinfections; and septic diseases. Several molecules of the presentinventions also exhibit impressive gains in potency againstMycobacterium tuberculosis and therefore of potential value in thetreatment of latent and recalcitrant mycobacterial infections such astuberculosis.

These findings have an important implication from the point of view ofthe systemic use of the compounds of the invention in view of theirsuperior potency, superior bactericidal activity, expanded biospectrum,better bioavailability and improved tolerability which are now enabledto be administered systemically in therapeutically effective doses.

Utilizing the compounds of the invention or the substantially opticallypure or optically pure isomers, the derivatives and salts thereof,whether in systemic or topical dosage form, results in clearerdose-related definitions of efficacy, diminished toxic effects andaccordingly an improved therapeutic index.

The present invention encompasses certain compounds, dosage forms, andmethods of administering the compounds to a human or other animalsubject. Specific compounds and compositions to be used in the inventionmust, accordingly, be pharmaceutically acceptable. As used herein, sucha “pharmaceutically acceptable” component is one that is suitable foruse with humans and/or animals without undue adverse side effects (suchas toxicity, irritation, and allergic response) commensurate with areasonable benefit/risk ratio.

The pharmaceutical compositions are prepared according to conventionalprocedures used by persons skilled in the art to make stable andeffective compositions. In the solid, liquid, parenteral and topicaldosage forms, an effective amount of the active compound or the activeingredient is any amount, which produces the desired results.

For the purpose of this invention the pharmaceutical compositions maycontain the active compounds of the invention, their derivatives, saltsand hydrates thereof, in a form to be administered alone, but generallyin a form to be administered in admixture with a pharmaceutical carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. Suitable carriers which can be usedare, for example, diluents or excipients such as fillers, extenders,binders, emollients, wetting agents, disintegrants, surface activeagents and lubricants which are usually employed to prepare such drugsdepending on the type of dosage form.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of the compound of the invention theirderivatives, salts and hydrates thereof. For example, oral, rectal,parenteral (subcutaneous, intramuscular, intravenous), transdermal,topical and like forms of administration may be employed. Dosage formsinclude (solutions, suspensions, etc) tablets, pills, powders, troches,dispersions, suspensions, emulsions, solutions, capsules, injectablepreparations, patches, ointments, creams, lotions, shampoos and thelike.

The prophylactic or therapeutic dose of the compounds of the invention,their derivatives, salts or hydrates thereof, in the acute or chronicmanagement of disease will vary with the severity of condition to betreated, and the route of administration. In addition, the dose, andperhaps the dose frequency, will also vary according to the age, bodyweight and response of the individual patient. In general, the totaldaily dose range, for the compounds of the invention, the derivatives,salts or hydrates thereof, for the conditions described herein, is fromabout 200 mg to about 1500 mg, in single or divided doses. Preferably, adaily dose range should be between about 400 mg to 1200 mg, in single ordivided dosage, while most preferably a daily dose range should bebetween about 500 mg to about 1000 mg in divided dosage. Whileintramuscular administration may be a single dose or up to 3 divideddoses, intravenous administration can include a continuous drip. It maybe necessary to use dosages outside these ranges in some cases as willbe apparent to those skilled in the art. Further, it is noted that theclinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual patient'sresponse. The term “an amount sufficient to eradicate such infectionsbut insufficient to cause undue side effects” is encompassed by theabove—described dosage amount and dose frequency schedule.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets, or tablets, or aerosol sprays, each containing a predeterminedamount of the active ingredient, as a powder or granules, or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Suchcompositions may be prepared by any of the methods of pharmacy, but allmethods include the step of bringing into association the activeingredient with the carrier, which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation. The compositions of the presentinvention include compositions such as suspensions, solutions, elixirs,aerosols, and solid dosage forms. Carriers as described in general aboveare commonly used in the case of oral solid preparations (such aspowders, capsules and tablets), with the oral solid preparations beingpreferred over the oral liquid preparations. The most preferred oralsolid preparation is tablets.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are employed. Examples of suitable carriersinclude excipients such as lactose, white sugar, sodium chloride,glucose solution, urea, starch, calcium carbonate, kaolin, crystallinecellulose and silicic acid, binders such as water, ethanol, propanol,simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate and polyvinylpyrrolidone, disintegrants such as dried starch, sodium alginate, agarpowder, laminaria powder, sodium hydrogen carbonate, calcium carbonate,Tween (fatty acid ester of polyoxyethylenesorbitan), sodium laurylsulfate, stearic acid monoglyceride, starch, and lactose, disintegrationinhibitors such as white sugar, stearic acid glyceryl ester, cacaobutter and hydrogenated oils, absorption promoters such as quaternaryammonium bases and sodium lauryl sulfate, humectants such as glyceroland starch, absorbents such as starch, lactose, kaolin, bentonite andcolloidal silicic acid, and lubricants such as purified talc, stearicacid salts, boric acid powder, polyethylene glycol and solidpolyethylene glycol.

The tablet, if desired, can be coated, and made into sugar-coatedtablets, gelatin-coated tablets, enteric-coated tablets, film-coatedtablets, or tablets comprising two or more layers.

If desired, tablets may be coated by standard aqueous or non-aqueoustechniques.

In molding the pharmaceutical composition into pills, a wide variety ofconventional carriers known in the art can be used. Examples of suitablecarriers are excipients such as glucose, lactose, starch, cacao butter,hardened vegetable oils, kaolin and talc, binders such as gum arabicpowder, tragacanth powder, gelatin, and ethanol, and disintegrants suchas laminaria and agar. In molding the pharmaceutical composition into asuppository form, a wide variety of carriers known in the art can beused. Examples of suitable carriers include polyethylene glycol, cacaobutter, higher alcohols, gelatin, and semi-synthetic glycerides.

A second preferred method is parenterally for intramuscular, intravenousor subcutaneous administration.

A third preferred route of administration is topically, for whichcreams, ointments, shampoos, lotions, dusting powders and the like arewell suited. Generally, an effective amount of the compound according tothis invention in a topical form is from about 0.1% w/w to about 10% w/wof the total composition. Preferably, the effective amount of thecompound of the invention is 1% w/w of the total composition.

In addition to the common dosage forms set out above, the compounds ofthe present invention may also be administered by controlled releasemeans and/or delivery devices such as those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123 and 4,008,719; thedisclosures of which are hereby incorporated by reference.

Desirably, each tablet contains from about 200 mg to about 1500 mg ofthe active ingredient. Most preferably, the tablet, cachet or capsulecontains either one of three dosages, about 200 mg, about 400 mg, orabout 600 mg of the active ingredient.

When the pharmaceutical composition is formulated into an injectablepreparation, in formulating the pharmaceutical composition into the formof a solution or suspension, all diluents customarily used in the artcan be used. Examples of suitable diluents are water, ethyl alcohol,polypropylene glycol, ethoxylated isostearyl alcohol, polyoxyethylenesorbitol, and sorbitan esters. Sodium chloride, glucose or glycerol maybe incorporated into a therapeutic agent.

The antimicrobial pharmaceutical composition may further containordinary dissolving aids, buffers, pain-alleviating agents, andpreservatives, and optionally coloring agents, perfumes, flavors,sweeteners, and other drugs. For topical application, there are employedas non-sprayable forms, viscous to semi-solid or solid forms comprisinga carrier compatible with topical application and having a dynamicviscosity preferably greater than water. Suitable formulations includebut are not limited to solutions, suspensions, emulsions, creams,ointments, powders, liniments, salves, aerosols, etc., which are, ifdesired, sterilized or mixed with auxiliary agents, e.g. preservatives,antioxidants, stabilizers, wetting agents, buffers or salts forinfluencing osmotic pressure, etc. For topical application, alsosuitable are sprayable aerosol preparations wherein the activeingredient preferably in combination with a solid or liquid inertcarrier material.

A specific embodiment of the invention is the preparation of storagestable compositions of the compounds of the invention of formula I. Suchstable compositions can be advantageously made through the use ofselective stabilizers. Different stabilizers are known to those skilledin the art of making pharmaceutical compositions. Of special utility formaking storage stable compositions of the compound of the invention offormula I, stabilizers such as disodium ethylenediaminetetraacetic acid(EDTA), tromethamine, cyclodextrins such as gamma-cyclodextrin,hydroxy-propyl-gamma-cyclodextrin have been found to be useful.

In a specific embodiment of the invention, the pharmaceuticalcompositions contain an effective amount of the active compounds of theinvention, its derivatives, salts or hydrates thereof described in thisspecification as hereinbefore described in admixture with apharmaceutically acceptable carrier, diluent or excipients, andoptionally other therapeutic ingredients.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of the composition of the presentinvention as well as their utility. It will be apparent to those skilledin the art that many modifications, both to materials and methods may bepracticed without departing from the purpose and scope of thisinvention.

The following preparations and examples illustrate the methods ofpreparation of the compounds of the invention and are provided only asexamples, but not to limit the scope of the compounds of the invention.

General Preparation for Synthesising 1-benzyl-3-alkyl-4-piperidones

A method for preparing a 3-alkyl substituted-1-benzyl-4-piperidonecomprising the steps of:

1) treating ethyl-1-benzyl-4-oxo-piperidine-3-carboxylate hydrochloridewith a base such as potassium tert-butoxide, potassium hydroxide,preferably potassium hydroxide in an organic solvent; such as diethylether, dioxane, tetrahydrofuran, N,N-dimethylformamide or mixturesthereof, preferably 1:1 mixture of tetrahydrafuran andN,N-dimethylformamide,

2) adding alkyl halide under stirring at a temperature between 25°C.-65° C., preferably 25° C.-40° C. for 1-12 hrs, preferably 2-3 hrs;and

3) heating with inorganic acid such as hydrochloric acid, sulfuric acid,preferably hydrochloric acid, in the presence of solvent such as water,dioxane, N,N-dimethylformamide, preferably water or dioxane at 80°C.-120° C., preferably 90° C.-110° C. for 5-36 hrs, preferably 24-36hrs, and isolating the product.

General Preparation for Synthesising1-benzyl-3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl-4-piperidones

A method for preparing a 3,3-dialkyl/3,5-dialkyl/3,3,5-trialkylsubstituted-1-benzyl-4-piperidone comprising the steps of:

1) treating 1-benzyl-4-piperidone orethyl-3-alkyl-1-benzyl-4-oxo-piperidine-3-carboxylate or3,3-dialkyl-1-benzyl-4-piperidones in an organic solvent such asdioxane, N,N-dimethylformamide, tetrahydrofuran, preferablytetrahydrofuran or dioxane with a base such as potassium tert-butoxide,sodium hydride, n-butyl lithium, preferably sodium hydride or potassiumtert-butoxide;

2) adding an alkyl halide selected from C1-C6 lower alkyl/alkenyliodides/bromides such as methyl iodide, ethyl iodides, allyl bromide,propargyl bromide etc or C1-C6 aralkyl iodides/bromides/chlorides suchas benzyl bromide, benzyl chloride etc under stirring at temperature abetween −10° C. to 45° C., preferably −10° C. to 35° C. for 12-24 hrs,preferably 12-16 hrs, and isolating the product.

General Preparation for Synthesising3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl-4-aminopiperidines

A method for preparing a 3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkylsubstituted-4-amino/methylamino/ethylamino/cyclopropylamino/dimethylamino-piperidinecomprising the steps of:

1) treating a 3-alkyl 3,3-dialkyl/3,5-dialkyl/3,3,5-trialkylsubstituted-1-benzyl-4-piperidone with an amine such as ammonium acetate(ammonia source), methylamine hydrochloride, ethylamine hydrochloride,cyclopropylamine, dimethylamine hydrochloride in an organic solvent suchas methanol, ethanol, preferably methanol, at a temperature between 10°C. to 35° C., preferably 20° C. to 35° C., for 1-6 hrs, preferably 3-4hrs;

2) adding sodium cyano borohydride at temperature between 0° C. to 60°C., preferably 0° C. to 35° C. and isolating the product by evaporatingthe solvent under vacuum;

3) treating the isolated product with a catalyst such as palladiumhydroxide, palladium on carbon or platinum, preferably palladium oncarbon, in an organic solvent, such as methanol, ethanol, ethyl acetate,preferably methanol in presence of hydrogen or hydrogen sources such ashydrogen gas, ammonium formate, cyclohexene, preferably hydrogen gas,ammonium formate, at temperature between 30° C. to 60° C., preferably30° C. to 45° C. and isolating the product.

Preparation 1 4-Amino-3-methylpiperidine Step-14-Amino-1-carbethoxy-3-methylpiperidine

Ethyl chloroformate (3.0 g, 26.7 mmol) was added to a stirred solutionof 1-benzyl-3-methyl-4-piperidinone (2.0 g, 9.85 mmol) in benzene (30ml) at ambient temperature. The obtained reaction mixture was refluxedwith stirring for 6 hr and concentrated to dryness to give1-carbethoxy-3-methyl-4-piperidone as oil. Yield 1.4 g (77%), C₉H₁₅NO₃,m/z 186 (M+1).

Ammonium acetate (5 g, 64.93 mmol) was added to the stirred solution of1-carbethoxy-3-methyl-4-piperidone (1.4 g, 7.56 mmol) in methanol (25ml) and stirring was continued for 3 hr at ambient temperature. Theresulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.5g, 7.93 mmol) was added to it. Cooling was removed after 10 min. andresulting mixture was stirred for 6 hr at ambient temperature. Thereaction mixture was concentrated to dryness, triturated with water,acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate toremove impurities. The aqueous layer was basified with 1 M sodiumhydroxide solution (pH˜10) and extracted with ethyl acetate. Ethylacetate extract was dried (Na₂SO₄) and concentrated to dryness tofurnish 4-amino-1-carbethoxy-3-methylpiperidine. Yield 1.0 g (72%),C₉H₁₈N₂O₂, m/z 187 (M+1), PMR (CDCl₃): 0.94 (dd, 3H), 1.22 (m, 1H), 1.26(t, 3H), 1.6 (m, 1H), 1.82 (m,1H), 2.4 (m,1H), 2.82 (m, 1H), 3.34 (m,2H), 3.64 (m, 1H) 4.14 (q, 2H).

Step-2 4-Amino-3-methylpiperidine

4-Amino-1-carbethoxy-3-methylpiperidine (1.0 g, 5.73 mmol) was suspendedin 5 M NaOH solution (10 ml), stirred at 120° C. for 6 hr, cooled,extracted with ethyl acetate, dried (Na₂SO₄) and concentrated to drynessto afford 4-amino-3-methylpiperidine. Yield 0.2 g (34%), C₆H₁₄N₂, m/z115 (M+1), PMR (CDCl₃): 0.94 (m, 3H), 1.22-1.8 (m, 3H), 1.88 (m, 1H),2.22 (m, 1H), 2.7 (m, 1H), 3.0 (m, 2H).

Preparation 2 4-Methylamino-3-methylpiperidine Step-11-Carbethoxy-4-methylamino-3-methylpiperidine

Methylamine hydrochloride (10 g, 148 mmol) was added to the stirredsolution of 1-carbethoxy-3-methyl-4-piperidone (7 g, 37.83 mmol)obtained as described in Preparation 1, in methanol (50 ml) followed by8.3 g (148 mmol) KOH. Stirring was continued for 3 hr at ambienttemperature. The resulting mixture was cooled at 0° C. and sodiumcyanoborohydride (3.0 g, 46.0 mmol) was added to it. Cooling was removedafter 10 min. and resulting mixture was stirred for 12 hr at ambienttemperature. The reaction mixture was concentrated to dryness,triturated with water, acidified with conc. HCl (pH 3˜4) and extractedwith ethyl acetate to remove impurities. The aqueous layer was basifiedwith 1 M sodium hydroxide solution (pH˜10) and extracted with ethylacetate. Ethyl acetate extract was dried (Na₂SO₄) and concentrated todryness to give 1-carbethoxy-4-methylamino-3-methylpiperidine. Yield 4.0g (50%), C₁₀H₂₀N₂O₂, m/z 201 (M+1), PMR (CDCl₃): 0.92 (dd, 3H), 1.26 (t,3), 1.54 (m, 1H), 2.1 (m, 2H), 2.34 (s, 3H), 2.62 (m, 1H), 2.86 (m, 1H),3.06 (m, 1H), 3.46 (m, 1H), 3.72 (m, 1H), 4.1 (q, 2H).

Step-2 4-Methylamino-3-methylpiperidine

1-Carbethoxy-4-methylamino-3-methylpiperidine (4.0 g, 18.34 mmol) wassuspended in 5 M NaOH solution (15 ml), stirred at 110° C. for 24 hr,cooled, extracted with ethyl acetate, dried (Na₂SO₄) and concentrated todryness to afford 4-methylamino-3-methyl-piperidine. Yield 1.8 g (77%),C₇H₁₆N₂, m/z 129 (M+1), PMR (CDCl₃): 0.92 (dd, 3H), 1.54 (m, 1H), 2.12(m, 2H), 2.38 (s, 3H), 2.6 (m, 1H), 2.8 (m, 1H), 3.02 (m,1H), 3.42(m,1H), 3.68 (m,1H).

Preparation 3 4-Ethylamino-3-methylpiperidine Step-11-Carbethoxy-4-ethylamino-3-methylpiperidine

Ethylamine hydrochloride (5 g, 61.34 mmol) was added to the stirredsolution of 1-carbethoxy-3-methyl-4-piperidone (3.5 g, 18.9 mmol)obtained as described in Preparation 1, in methanol (30 ml) followed by3.43 g (61.34 mmol) KOH. Stirring was continued for 3 hr at ambienttemperature. The resulting mixture was cooled at 0° C. and sodiumcyanoborohydride (1.4 g, 22.22 mmol) was added to it. Cooling wasremoved after 10 min. and resulting mixture was stirred for 16 hr atambient temperature. The reaction mixture was concentrated to dryness,triturated with water, acidified with conc. HCl (pH 3˜4) and extractedwith ethyl acetate to remove impurities. The aqueous layer was basifiedwith 1 M sodium hydroxide solution (pH˜10) and extracted with ethylacetate. Ethyl acetate extract was dried (Na₂SO₄) and, concentrated todryness to give 1-carbethoxy-4-ethylamino-3-methylpiperidine. Yield 2.3g (54%), C₁₁H₂₂N₂O₂, m/z 215 (M+1).

Step-2 4-Ethylamino-3-methylpiperidine

1-Carbethoxy-4-ethylamino-3-methylpiperidine (2.3 g, 10.74 mmol) wassuspended in 5 M NaOH solution (15 ml), stirred at 110° C. for 120 hr,cooled, extracted with ethyl acetate, dried (Na₂SO₄) and concentrated todryness to afford 4-ethylamino-3-methylpiperidine. Yield 0.7 g (46%),C₈H₁₈N₂, m/z 143, (M+1).

Preparation 4 4-Cyclopropylamino-3-methylpiperidine Step-11-Carbethoxy-4-cyclopropylamino-3-methylpiperidine

Cyclopropylamine (10 g, 169.5 mmol) was added to the stirred solution of1-carbethoxy-3-methyl-4-piperidone (7.0 g, 37.83 mmol) obtained asdescribed in Preparation 1, in methanol (50 ml) and stirring wascontinued for 12 hr at ambient temperature. The resulting mixture wascooled at 0° C. and sodium cyanoborohydride (3.0 g, 46.0 mmol) was addedto it. Cooling was removed after 10 min. and stirring was continued for12 hr at ambient temperature. The reaction mixture was concentrated todryness, triturated with water, acidified with conc. HCl (pH 3˜4) andextracted with ethyl acetate to remove impurities. The aqueous layer wasbasified with 1 M sodium hydroxide solution (pH˜10) and extracted withethyl acetate. Ethyl acetate extract was dried (Na₂SO₄) and concentratedto dryness to afford 1-carbethoxy4-cyclopropylamino-3-methylpiperidine.Yield 6.0 g (70%), C₁₂H₂₂N₂O₂, m/z 227 (M+1), PMR (CDCl₃): 0.38 (m, 4H),0.88 (dd, 3H), 1.28 (t, 3H), 1.54 (m, 1H), 2.06 (m, 2H), 2.32 (m, 1),2.48 (m, 1H), 2.84 (m, 1H), 3.06 (m, 1H), 3.72 (m, 1H), 3.88-4.24 (m,2H).

Step-2 4-Cyclopropylamino-3-methylpiperidine

1-Carbethoxy-4-cyclopropylamino-3-methylpiperidine (6.0 g, 26.66 mmol)was suspended in 5 M NaOH solution (20 ml), stirred at 130° C. for 120hr, cooled and extracted with ethyl acetate. Ethyl acetate extract wasdried (Na₂SO₄) and concentrated to dryness to afford a mixture ofstarting material (3.0 g) and 4-cyclopropylamino-3-methylpiperidine,which were separated by silica column chromatography. Yield 1.0 g (35%),C₉H₁₈N₂, m/z 155, (M+1).

Preparation 5 4-Dimethylamino-3-methylpiperidine Step-11-Carbethoxy-4-dimethylamino-3-methylpiperidine

Paraformaldehyde (5.1 g) was added to the stirred solution of4-amino-1-carbethoxy-3-methylpiperidine (3.5 g, 18.8 mmol) in methanol(100 ml) at 0° C. and sodium cyanoborohydride (1.7 g, 27.0 mmol) wasadded to it. Then, acetic acid (1 ml) was added to the resulting mixtureand stirring was continued for 96 hr at ambient temperature. Thereaction mixture was concentrated to dryness, triturated with water,acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate toremove impurities. The aqueous layer was basified with 1 M sodiumhydroxide solution (pH˜10) and extracted with ethyl acetate. Ethylacetate extract was dried (Na₂SO₄) and concentrated to dryness to give1-carbethoxy-4-dimethylamino-3-methylpiperidine. Yield 3.5 g (88%),C₁₁H₂₂N₂O₂, m/z 215 (M+1).

Step-2 4-Dimethylamino-3-methylpiperidine

1-Carbethoxy-4-dimethylamino-3-methylpiperidine (3.5 g, 16.3 mmol) wassuspended in 5 M NaOH solution (20 ml), stirred at 110° C. for 48 hr,cooled, extracted with ethyl acetate, dried (Na₂SO₄) and concentrated todryness to afford 4-dimethylamino-3-methylpiperidine. Yield 1.0 g (43%),C₈H₁₈N₂, m/z 143 (M+1), PMR (CDCl₃): 0.96 (dd, 3H), 1.3 (m, 1H), 1.5 (m,1H), 1.74 (m, 1H), 2.08 (m, 1H), 2.24 (s, 6H), 2.38 (m, 1H), 2.61 (bs,1H, D₂O exchangeable), 2.86 (m, 1H), 3.16 (m, 1H), 3.68 (m, 1H).

Preparation 6 4-Amino-3-ethylpiperidine

Ethyl chloroformate (37.49 g, 346 mmol) was added to a stirred solutionof 1-benzyl-3-ethyl-4-piperidone (24.0 g, 110 mmol) in benzene (200 ml)at ambient temperature. The obtained reaction mixture was refluxed withstirring for 16 hr and concentrated to dryness to give1-carbethoxy-3-ethylpiperidin-4-one as oil. Yield 21 g (96%), C₁₀H₁₇NO₃,m/z 200 (M+1).

Ammonium acetate (33 g) was added to the stirred solution of1-carbethoxy-3-ethyl-4-piperidinone (8.2 g, 41 mmol) in methanol (125ml) and stirring was continued for 3 hr at ambient temperature. Theresulting mixture was cooled at 0° C. and sodium cyanoborohydride (2.5g, 39 mmol) was added to it. Cooling was removed after 10 min. andresulting mixture was stirred for 6 hr at ambient temperature. Thereaction mixture was concentrated to dryness, triturated with water,acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate toremove impurities. The aqueous layer was basified with 1 M sodiumhydroxide solution (pH˜10) and extracted with ethyl acetate. Ethylacetate extract was dried (Na₂SO₄) and concentrated to dryness tofurnish crude 4-amino-1-carbethoxy-3-ethylpiperidine, which was used assuch in the next step. 4-Amino-1-carbethoxy-3-ethylpiperidine wassuspended in 5 M NaOH solution (36 ml), stirred at 120° C. for 120 hr,cooled, extracted with ethyl acetate, dried (Na₂SO₄) and concentrated todryness to afford 4-amino-3-ethylpiperidine. Yield 3.1 g (59.6%),C₇H₁₆N₂, m/z 129 (M+1).

Preparation 7 4-Methylamino-3-ethylpiperidine

Methylamine hydrochloride (17 g, 252 mmol) was added to the stirredsolution of 1-carbethoxy-3-ethyl-4-piperidone (10 g, 50 mmol) inmethanol (150 ml) followed by 14.1 g (252 mmol) KOH. Stirring wascontinued for 3 hr at ambient temperature. The resulting mixture wascooled at 0° C. and sodium cyanoborohydride (4.72 g, 75 mmol) was addedto it. Cooling was removed after 10 min. and resulting mixture wasstirred for 12 hr at ambient temperature. The reaction mixture wasconcentrated to dryness, triturated with water, acidified with conc. HCl(pH 3˜4) and extracted with ethyl acetate to remove impurities. Theaqueous layer was basified with 1 M sodium hydroxide solution (pH˜10)and extracted with ethyl acetate. Ethyl acetate extract was dried(Na₂SO₄) and concentrated to dryness to give crude1-carbethoxy-4-methylamino-3-ethylpiperidine. The obtained crude1-carbethoxy-4-methylamino-3-ethylpiperidine was suspended in 7 M NaOHsolution (50 ml), stirred at 110° C. for 230 hr, cooled, extracted withethyl acetate, dried (Na₂SO₄) and concentrated to dryness to afford4-methylamino-3-ethyl-piperidine. Yield 3.5 g (50%), C₈H₁₈N₂, m/z 142(M+1).

Preparation 8 4-Cyclopropylamino-3-ethylpiperidine

Cyclopropylamine (14.25 g, 250 mmol) was added to the stirred solutionof 1-carbethoxy-3-ethyl-4-piperidone (10 g, 50 mmol) in methanol (100ml) and stirring was continued for 12 hr at ambient temperature. Theresulting mixture was cooled at 0° C. and sodium cyanoborohydride (3.9g, 62 mmol) was added to it. Cooling was removed after 10 min. andstirring was continued for 12 hr at ambient temperature. The reactionmixture was concentrated to dryness, triturated with water, acidifiedwith conc. HCl (pH 3˜4) and extracted with ethyl acetate to removeimpurities. The aqueous layer was basified with 1 M sodium hydroxidesolution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extractwas dried (Na₂SO₄) and concentrated to dryness to afford crude1-carbethoxy-4-cyclopropylamino-3-ethyl piperidine. The obtained crude1-carbethoxy-4-cyclopropylamino-3-ethylpiperidine was suspended in 7 MNaOH solution (30 ml), stirred at 130° C. for 160 hr, cooled andextracted with ethyl acetate. Ethyl acetate extract was dried (Na₂SO₄)and concentrated to dryness to afford4-cyclopropylamino-3-ethyl-piperidine. Yield 5.7 g (67%), C₁₀H₂₀N₂, m/z169, (M+1).

Preparation 9 4-Dimethylamino-3-ethylpiperidine

Sodium cyanoborohydride (3.2 g, 50.8 mmol) was added to the stirredsuspension of N-tert.-butoxycarbonyl-3-ethyl-4-piperidone (8 g, 35mmol), N,N-dimethylamine hydrochloride (14 g, 172 mmol) and KOH (9.6 g,172 mmol) in methanol (50 ml) at 0° C. The resulting mixture was stirredfor 4 hr at ambient temperature. The reaction mixture was concentratedto dryness, triturated with water, acidified with conc. HCl (pH 3˜4) andextracted with ethyl acetate to remove impurities. The aqueous layer wasbasified with 1 M sodium hydroxide solution (pH˜10) and extracted withethyl acetate. Ethyl acetate extract was dried (Na₂SO₄) and concentratedto dryness to give 4-dimethylamino-3-ethylpiperidine. Yield 2.3 g (37%),C₉H₂₀N₂, m/z 157 (M+1).

Preparation 10 4-Amino-3,3-dimethylpiperidine Step 11-Benzyl-3,3-dimethyl-4-piperidone Method-A

-   -   To a solution of 1-benzyl-4-piperidone (1 kg, 5.3 mol) in 7        liter THF, was added simultaneously potassium tert-butoxide        (1.25 kg, 11.16 mol) in eight equal lots, and methyl iodide (1.5        kg, 10.56 mol) diluted with 1 liter THF, over a period of four        hours between temperature 0 to 10° C. The reaction mixture was        slowly allowed to warm upto to 35° C. and maintained for 4        hours. The reaction mixture was diluted with 4 liter saturated        aqueous sodium chloride solution. The organic layer was        separated. The aqueous layer was washed with 2.0 liter        chloroform. Combined organic layer was concentrated to provide a        crude product in 1.23 kg quantity.    -   The crude product was distilled at 3 mm vacuum, and 160° C.        fraction distillate was collected in a quantity of 800 gm. To        the distillate, 1 liter concentrated HCl was added to provide a        clear solution. The solution obtained was concentrated to        dryness. The solid obtained was recrystallised from 2 liter        isopropanol to afford hydrochloride salt of        1-benzyl-3,3-dimethyl-4-piperidone (720 gm).    -   The solid was dissolved in 2 liter water and treated with 800 ml        aqueous ammonia. The basic solution obtained was extracted with        2×2 liter CHCl₃. Concentration of the combined organic layer        afforded 1-benzyl-3,3-dimethyl-4-piperidone (490 gm, 42% yield)        having spectral data as given below:    -   C14H19NO m/z=218 (ES+1)    -   PMR (CDCl₃): 1.18 (s, 6H); 2.40 (s, 2H); 2.45 (t, 2H); 2.65 (t,        2H); 3.60 (s, 2H); 7.38 (m, 5H).

Method-B

-   -   1-Benzyl-4-piperidone (100 gm, 0.53 mol) diluted with 100 ml THF        was added to a suspension of 60% NaH (42 g, 1.05 mol) in 700 ml        THF at −10 to −5° C. The mixture was stirred for 1 hour and        methyl iodide (150 gm, 1.06 mol) diluted in 50 ml THF was added,        maintaining the temperature between −3 to −10° C. The resultant        mixture was stirred. Ethyl acetate (800 ml) was added to the        reaction mixture followed addition of 300 ml water. The organic        layer was separated washed with 2×300 ml water and concentrated        under vacuum to obtain a syrup. The syrup was triturated with        200 ml hexane. the mass was filtered at room temperature over        celite and the filtrate concentrated to afford a 121 gm of crude        compound. The crude compound upon high vacuum distillation        afforded 85 g distillate. To the distillate (50 gm) was charged        50 ml of concentrated hydrochloric acid. The suspension was        stirred for 15 minutes and hydrochloric acid was evaporated        under vacuum to obtain a thick residue. Isopropanol (50 ml) was        added to this residue and was evaporated under vacuum to obtain        a solid. The solid was dissolved in 200 ml isopropanol under        reflux and stirring, and cooled under stirring to effect        crystallization. The crystalline solid was filtered under        suction at 20-30° C. to give a white crystalline compound as        hydrochloride salt of 1-benzyl-3,3-dimethyl-4-piperidone. The        solid was dissolved in 100 ml water and made alkaline with        aqueous ammonia solution to pH 10-11. Alkaline aqueous phase was        extracted with 50 ml chloroform thrice. Combined organic extract        was washed with water, dried over sodium sulfate and then        evaporated under vacuum to afford 28 g (80%) compound as an oil.    -   m/z (M+1) 218.    -   NMR (CDCl₃): 1.18 (s, 6H,); 2.40 (s, 2H); 2.45(t, 2H); 2.65 (t,        2H); 3.60 (s, 2H); 7.38 (m,5H).

Step-2 4-Amino-3,3-dimethylpiperidine

-   -   Ammonium acetate (3.5 g, 45.45 mmol) was added to the stirred        solution of 1-benzyl-3,3-dimethyl-4-piperidone (2.0 g, 9.2        mmol), in methanol (20 ml) and stirring was continued for 3 hr        at ambient temperature. The resulting mixture was cooled at        0° C. and sodium cyanoborohydride (0.58 g, 9.2 mmol) was added.        Cooling was removed after 10 min. and resulting mixture was        stirred for 6 hr at ambient temperature. The reaction mixture        was concentrated to dryness, triturated with water, acidified        with conc. HCl (pH 3˜4) and extracted with ethyl acetate to        remove impurities. The aqueous layer was basified with 1 M        sodium hydroxide solution (pH˜10) and extracted with ethyl        acetate. Ethyl acetate extract was dried (Na₂SO₄) and        concentrated to dryness to furnish 4-amino-1-benzyl-3,3-dimethyl        piperidine. Yield 1.6 g (77%), C₁₄H₂₂N₂, m/z 219 (M+1), PMR        (CDCl₃): 0.84 (s, 3H), 0.98 (s, 3H), 1.48 (bs, 2H, D₂O        exchangeable), 1.66 (m, 2H), 2.04 (m, 2H), 2.42 (m, 2H), 2.86        (m, 1H), 3.46 (dd, 2H), 7.32 (m, 5H).    -   A mixture of 20% Pd(OH)₂ on carbon (0.3 g) and        4-amino-1-benzyl-3,3-dimethylpiperidine (1.6 g, 7.33 mmol) in        methanol (25 ml) was stirred in hydrogen atmosphere (1 atm.) at        30° C. for 6 hr. The catalyst was filtered off, washed with        methanol and filtrate was concentrated to dryness to afford        4-amino-3,3-dimethylpiperidine. Yield 0.7 g (75%), C₇H₁₆N₂, m/z        129 (M+1), PMR (CDCl₃): 0.9 (s, 6H), 1.5 (m, 2H), 1.58 (bs, 2H,        D₂O exchangeable), 2.26-2.68 (m, 4H), 3.06 (m, 1H), 3.52 (bs,        1H, D₂O exchangeable).

Preparation 11 4-Methylamino-3,3-dimethylpiperidine

-   -   Potassium hydroxide (12.85 g, 230 mmol) was added to the stirred        solution of methylamine hydrochloride (15.5 g, 230.0 mmol) in        methanol (100 ml) and stirring was continued for 30 min at        30° C. 1-Benzyl-3,3-dimethyl-4-piperidone (5 g, 23.0 mmol), was        added to the resulting mixture and stirred for 6 hr. Sodium        cyanoborohydride (1.45 g, 23.0 mmol) was added to it and        reaction mixture was stirred for 15 hr. The reaction mixture was        concentrated to dryness, triturated with water, extracted with        chloroform, dried (Na₂SO₄) and concentrated to give        1-benzyl-4-methylamino-3,3-dimethylpiperidine. Yield 5.3 g        (99%), C₁₅H₂₄N₂, m/z 233 (M+1), PMR (CDCl₃): 0.9 (s, 3H), 1.0        (s, 3H), 1.38 (m, 2H), 1.54 (bs, 1H, D₂O exchangeable), 1.68-2.1        (m, 4H), 2.4 (s, 3H), 2.86 (m, 1H), 3.4 (dd, 2H), 7.3 (m, 5H).    -   A mixture of 20% Pd(OH)₂ on carbon (0.15 g) and        1-benzyl-4-methylamino-3,3-dimethylpiperidine (0.5 g, 2.1 mmol)        in methanol (10 ml) was stirred in hydrogen atmosphere (1 atm.)        at 60° C. for 6 hr. The catalyst was filtered off, washed with        methanol and filtrate was concentrated to dryness to afford        4-methylamino-3,3-dimethyl-piperidine. Yield 0.3 g (99%),        C₈H₁₈N₂, m/z 143 (M+1), PMR (CDCl₃): 0.88 (s, 6H), 1.24 (m, 2H),        1.8 (bs, 2H, D₂O exchangeable), 1.8 (m, 1H), 2.1 (m, 1H), 2.4        (s, 3H), 2.6 (d, 2H), 2.86 (m, 1H).

Preparation 12 4-Ethylamino-3,3-dimethylpiperidine

-   -   Potassium hydroxide (4.6 g, 83.0 mmol) was added to the stirred        solution of ethylamine hydrochloride (6.8 g, 83.0 mmol) in        methanol (70 ml) and stirring was continued for 30 min at 30° C.        1-benzyl-3,3-dimethyl-4-piperidone (3.5 g, 16.6 mmol)), was        added to the resulting mixture and stirred for 6 hr. Sodium        cyanoborohydride (1.0 g, 16.6 mmol) was added to it and reaction        mixture was stirred for 15 hr. The reaction mixture was        concentrated to dryness, triturated with water, extracted with        chloroform, dried (Na₂SO₄) and concentrated to give        1-benzyl-4-ethylamino-3,3-dimethylpiperidine. Yield 3.8 g (88%),        C₁₆H₂₆N₂, m/z 247 (M+1), PMR (CDCl₃): 0.9 (s, 3H), 1.06 (s, 3H),        1.18-1.38 (m, 5H), 1.64-2.8 (m, 6H), 2.94 (m, 1H), 3.44 (dd,        2H), 7.2 (m, 5H),    -   A mixture of 20% Pd(OH)₂ on carbon (0.4 g) and        1-benzyl-4-ethylamino-3,3-dimethylpiperidine (1.3 g, 5.3 mmol)        in methanol (10 ml) was stirred in hydrogen atmosphere (1 atm.)        at ambient temperature for 15 hr. The catalyst was filtered off,        washed with methanol and filtrate was concentrated to dryness to        afford 4-ethylamino-3,3-dimethylpiperidine. Yield 0.8 g (97%),        C₉H₂₀N₂, m/z 157 (M+1), PMR (CDCl₃): 0.9 (s, 3H), 1.06 (s, 3H),        1.18-1.38 (m, 5H), 1.85 (bs, 2H, D₂O exchangeable), 1.64-2.8 (m,        6H), 2.94 (m, 1H).

Preparation 13 4-Cyclopropylamino-3,3-dimethylpiperidine

-   -   1-Benzyl-3,3-dimethyl-4-piperidone (10.0 g, 46.0 mmol), was        added to the stirred solution cyclopropylamine (13.1 g, 230.0        mmol) in methanol (150 ml) and stirred for 6 hr. Sodium        cyanoborohydride (2.9 g, 46.0 mmol) was added to it and reaction        mixture was stirred for 15 hr. The reaction mixture was        concentrated to dryness, triturated with water, extracted with        chloroform, dried (Na₂SO₄) and concentrated. The obtained crude        product was purified over silica gel column. Eluted from 5%        ethyl acetate in hexane gave        1-benzyl-4-cyclopropylamino-3,3-dimethyl piperidine. Yield 8.0 g        (67.3%), C₁₇H₂₆N₂, m/z 259 (M+1), PMR (CDCl₃): 0.4 (m, 2H), 0.82        (s, 3H), 1.06 (s, 3H), 1.16 (m, 2H), 1.5 (bs, 1H, D₂O        exchangeable), 1.7 (m, 2H), 1.9-2.95 (m, 5H), 3.3-3.6 (m, 3H),        7.22 (m, 5H).    -   A mixture of 20% Pd(OH)₂ on carbon (0.5 g) and        1-benzyl-4-cyclopropyl-amino-3,3-dimethylpiperidine (2.0 g, 7.7        mmol) in methanol (20 ml) was stirred in hydrogen atmosphere (1        atm.) at 60° C. for 48 hr. The catalyst was filtered off, washed        with methanol and filtrate was concentrated to dryness to afford        4-cyclopropylamino-3,3-dimethylpiperidine. Yield 1.2 g (92%),        C₁₀H₂₀N₂, m/z 169 (M+1), PMR (CDCl₃): 0.42 (m, 2H), 0.84 (s,        3H), 0.9 (s, 3H), 1.22 (m, 2H), 1.7 (bs, 2H), D₂O exchangeable),        1.94 (m, 2H), 2.1-2.72 (m, 5H), 3.08 (m, 1H).

Preparation 14 4-Dimethylamino-3,3-dimethylpiperidine

-   -   Formaldehyde solution (47%, 10 g) was added to the stirred        solution of 4-amino-1-benzyl-3,3-dimethylpiperidine (2.0 g, 9.2        mmol) in methanol (20 ml) at 0° C. and sodium cyanoborohydride        (0.5 g, 9.2 mmol) was added to it. Then, acetic acid (2 ml) was        added to the resulting mixture and stirring was continued for 24        hr at ambient temperature. The reaction mixture was concentrated        to dryness, triturated with water, acidified with conc. HCl (pH        3˜4) and extracted with ethyl acetate to remove impurities. The        aqueous layer was basified with 1 M sodium hydroxide solution        (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract        was dried (Na₂SO₄) and concentrated to give        1-benzyl-4-dimethylamino-3,3-dimethylpiperidine. Yield 1.9 g (84        %), C₁₆H₂₆N₂, m/z 247 (M+1).    -   A mixture of 20% Pd(OH)₂ on carbon (0.3 g) and        1-benzyl-4-dimethylamino-3,3-dimethylpiperidine (4.5 g, 6.0        mmol) in methanol (20 ml) was stirred in hydrogen atmosphere (1        atm.) for 48 hr at room temperature. The catalyst was filtered        off, washed with methanol and filtrate was concentrated to        afford 4-dimethylamino-3,3-dimethylpiperidine. Yield 1.6 g        (95%), C₉H₂₀N₂, m/z 157 (M+1).

Preparation 15 4-Carbethoxyamino-3,3-dimethylpiperidine

-   -   Ethyl chloroformate (2 ml) was added to a stirred solution of        4-amino-1-benzyl-3,3-dimethylpiperidine (1.6 g, 7.33 mmol) and        triethylamine (2 ml) in methylene chloride (25 ml) at ambient        temperature, stirring was continued for 1 hr concentrated to        dryness, triturated with water, extracted with ethyl acetate,        dried (Na₂SO₄) and concentrated to give        1-benzyl-4-carbethoxyamino-3,3-dimethyl piperidine as oil. Yield        1.3 g (62%), C₁₇H₂₆N₂O₂, m/z 291 (M+1), PMR (CDCl₃): 0.98 (s,        3H), 1.2 (t, 6H), 1.78 (m, 2H), 2.42 (m, 2H), 2.82 (m, 2H), 3.6        (d, 2H), 3.9 (m, 1H), 4.1 (q, 2H), 4.8 (bs, 1H), 7.54 (m, 5H).    -   A mixture of 20% Pd(OH)₂ on carbon (0.3 g) and        1-benzyl-4-carbethoxyamino-3,3-dimethylpiperidine (1.3 g, 4.48        mmol) in methanol (15 ml) was stirred in hydrogen atmosphere (1        atm.) at 30° C. for 3 hr. The catalyst was filtered off, washed        with methanol and filtrate was concentrated to dryness to afford        4-carbethoxyamino-3,3-dimethylpiperidine. Yield 0.8 g (90%),        C₁₀H₂₀N₂O₂, m/z 201 (M+1).

Preparation 16 4-Acetylamino-3,3-dimethylpiperidine

-   -   Acetic anhydride (3 ml) was added to a stirred solution of        4-amino-1-benzyl-3,3-dimethylpiperidine (2.0 g, 9.17 mmol) in        pyridine (5 ml) and stirred for 1 hr. The reaction mixture was        concentrated to furnish 4-acetylamino-1-benzyl-3,3-dimethyl        piperidine as an oil. Yield 1.8 g (76%), C₁₆H₂₄N₂O, m/z 261        (M+1), PMR (CDCl₃): 0.84 (s, 3H), 0.98 (s, 3H), 1.64 (m, 2H),        2.02 (s, 3H), 2.12 (m, 2H), 2.44 (d, 1H), 2.84 (d, 1H), 3.44 (d,        2H), 3.7 (m, 1H), 5.3 (bs, 1H), 7.31 (m, 5H).    -   A mixture of 20% Pd(OH)₂ on carbon (0.3 g) and        4-acetylamino-1-benzyl-3,3-dimethyl piperidine (1.8 g, 6.92        mmol) in methanol (20 ml) was stirred in hydrogen atmosphere (1        atm.) at 35° C. for 6 hr. The catalyst was filtered off, washed        with methanol and filtrate was concentrated to dryness to afford        4-acetylamino-3,3-dimethylpiperidine. Yield 1.0 g (90%),        C₉H₁₈N₂O, m/z 171 (M+1).

Preparation 17 3,3-Dimethyl-4-piperidone

-   -   1-Benzyl-3,3-dimethyl-4-piperidone 275 g (1.26 mol), was        dissolved in 1.0 L. methanol. The solution was transferred to a        Parr reactor after adding 10% palladium on carbon (25 g). The        reaction mixture was stirred under 300 psi hydrogen pressure at        60° C. until chromatography showed complete conversion. The        reaction mixture was filtered and the residue washed with        methanol (200 ml). The filtrate was concentrated to dryness to        afford 3,3-dimethyl-4-piperidone (158 g) which was used as such        for the preparation of either        4-benzyloxycarbonylamino-3,3-dimethylpiperidine or        4-t-butyloxycarbonylamino-3,3-dimethylpiperidine.

Preparation 18 (±)-4-Benzyloxycarbonylamino-3,3-dimethylpiperidineStep-1 1-^(t-)Butyloxycarbonyl-3,3-dimethyl-4-piperidone

-   -   Di-t-butyldicarbonate (430 g, 1.97 mol) was added to a stirred        solution of 3,3-dimethyl-4-piperidone (262 g, 2.06 mol) and        triethylamine (175 g, 1.73 mol) in 600 ml dichloromethane at        0-10° C. over a period of 1 hour. Cooling was removed and the        reaction mixture was stirred at 20-30° C. for 30 min. The        reaction mixture was concentrated to dryness and the residue was        triturated with hexane (250 ml) and filtered to give        1-t-butyloxycarbonyl-3,3-dimethyl-4-piperidone (352 g) in 76%        yield. m/z (M+1) 228.    -   NMR(CDCl₃): 0.8 (s, 3H); 0.95 (s,3H); 1.50 (s, 9H); 1.5-1.8 (m,        2H); 2.5-2.9 (m, 2H); 3.4-3.8 (m, 2H); 4.05 (bs, 1H), 4.6        (d,1H), 5.05(s, 2H), 7.4 (s,5H).

Step-2 4-Amino 1-^(t-)butyloxycarbonyl-3,3-dimethylpiperidine

-   -   Ammonium acetate (700 g, 9.09 mol) was added to a stirred        solution of 1-^(t)-butyloxy carbonyl-3,3-dimethyl-4-piperidone        (352 g, 1.55 mol) in methanol (1.0 L). The suspension was        stirred for 3 hr at 20-30° C. The reaction mixture was cooled to        0° C. and sodiumcyanoborohydride (45 g, 0.71 mol) was added        portion wise over 30 minutes. Cooling was removed and the        suspension was stirred for 12 hr at 20-30° C. The reaction        mixture was concentrated to dryness, stirred with water (2.0 L)        and extracted with 1.0 L×3 dichloromethane. Combined organic        extract was washed with water and dried over sodium sulfate.        Evaporation of organic solvent afforded the product.

Step-34-Benzyloxycarbonylamino-1-^(t-)butyloxycarbonyl-3,3-dimethylpiperidine

-   -   Benzyl chloroformate (50% in toluene, 450 ml, 1.57 mol) was        added to a stirred suspension of        4-amino-1-^(t)-butyloxycarbonyl-3,3-dimethylpiperidine (365 g)        as prepared above and NaHCO₃ (150 g, 1.78 mol) in dry        tetrahydrofuran (1.5 L). The reaction mixture was stirred for 20        hr at 35° C. The reaction mixture was diluted with 3.5 L water        and was extracted with 2.0 L×2 ethyl acetate. Combined organic        extract was washed with water, dried over Na₂SO₄ and        concentrated to dryness. The residue was subjected to        chromatography on a silica gel column to give        4-benzyloxycarbonylamino-1-^(t-)butyloxycarbonyl-3,3-dimethylpiperidine        in 63% (350 g) yield. m/z 363 (M+1).    -   NMR(CDCl₃): 0.8 (s, 3H); 0.95 (s, 3H); 1.5 (s, 9H); 1.5-1.8 (m,        2H); 2.5-2.9 (m, 2H); 3.4-3.8 (m, 2H); 4.05 (bs,1H); 4.6 (d,        1H); 5.05 (s, 2H); 7.4 (s, 5H)

Step-4 4-Benzyloxycarbonylamino-3,3-dimethylpiperidine

-   -   6 N HCl (200 ml) was added to a stirred solution of        4-benzyloxycarbonylamino-1-^(t)-butyloxycarbonyl-3,3-dimethylpiperidine        (350 g, 0.96 mol) in dioxane (200 ml). The resulting mixture was        stirred for 1 hr and concentrated to dryness. The resultant        residue was treated with water (3.0 L) water and was extracted        with 1.0 L×2 ethyl acetate. The aqueous layer was basified with        2 M aqueous NaOH and extracted with 2.5 L×2 dichloromethane.        Combined organic extract was washed with water, dried over        Na₂SO₄ and concentrated to afford        4-benzyloxycarbonylamino-3,3-dimethylpiperidine in 89% (224 g)        yield.    -   m/z (M+1) 263.    -   NMR (CDCl₃): 0.88 (s, 6H); 1.2-1.5 (m, 2H); 1.6-1.8 (m, 1H);        2.4-2.7 (m, 3H); 2.9-3.1 (m, 1H); 3.4-3.6 (m, 1H); 4.7 (s, 1H),        5.1 (s, 2H); 7.40 (s, 5H).

Preparation 19 (+) and(−)-4-^(t)-Butyloxycarbonylamino-3,3-dimethylpiperidine Step-11-Benzyloxycarbonyl-3,3-dimethyl-4-piperidone Method A

-   -   3,3-dimethyl-4-piperidone (157 g, 1.24 mol) was dissolved in        750 L. tetrahydrofuran and was charged with solid NaHCO₃ (115 g,        1.37 mol). The reaction mixture was stirred and under stirring        addition of 50% benzyl chloroformate in toluene (470 ml, 1.37        mol) was made at 0 to 10° C. temperature. To the reaction        mixture 1.0 L water was added and the resulting mixture was        extracted with 500 ml×3 ethyl acetate. Combined organic extract        was washed with water, dried over sodium sulfate and        concentrated in vacuo to give a residue which was subjected to        silica gel column chromatography to give 272 g titled compound.    -   m/z (M+1) 262.    -   NMR(CDCl₃): 1.18 (s, 6H); 2.50 (t, 2H); 3.50(s, 2H); 3.80 (t,        2H); 5.20 (s, 2H); 7.40 (s,5H).

Method B

-   -   1-Benzyl-3,3-dimethyl-4-piperidone (255 g, 1.175 mol) was        dissolved in 800 ml toluene. To the clear solution was charged        50% benzyl chloroformate in toluene (441 ml, 1.29 mol). The        reaction mixture was stirred at temperature between 80-85° C.        for 4-5 hrs. The reaction mixture was concentrated under vacuum.        Crude product was purified by silica gel column chromatography        to give 292 g (95%) titled compound. m/z (M+1) 262.    -   NMR (CDCl₃): 1.18 (s, 6H); 2.50 (t, 2H); 3.50(s, 2H); 3.80 (t,        2H); 5.20 (s, 2H); 7.40 (s,5H).

Step-2 4-Amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine

-   -   1-Benzyloxycarbonyl-3,3-dimethyl-4-piperidone (290 g, 1.11 mol)        was dissolved in methanol (1.5 L) and under stirring addition of        ammonium acetate (600 g, 7.80 mol ) was made at 30-35° C. The        reaction mixture was stirred for 5 hrs. Sodium cyanoborohydride        (35 g, 0.55 mol) was added portion wise to the suspension over        0.5 hrs by maintaining temperature between 0-10° C. The reaction        mixture was stirred for 6-7 hrs. After completion of reaction,        solvent was evaporated under reduced pressure and addition of        3.00 L water was made under stirring. The reaction mixture was        stirred for 15 minutes. It was extracted with 1.5 L×2 CHCl₃.        Combined organic extract was evaporated under vacuum. The        residue was dissolved in 3 N HCl till pH 1 and was extracted        with 500 ml×2 dichloromethane. The aqueous layer was basified        with 300 ml aqueous ammonia solution (23-25%) to pH 10-11 and        then was extracted with 1.5 L×3 dichloromethane. Combined        organic extract was washed with water and was dried over sodium        sulfate. Evaporation of organic solvent afforded 225 g (77%)        title compound.    -   m/z (M+1) 263.    -   NMR (CDCl₃) D₂O exchange: 0.80 (s, 3H); 0.98 (s, 3H); 1.40-1.78        (m, 2H); 2.50 (dt, 2H); 2.90 (m, 1H); 3.80 (t,1H); 4.18 (t, 1H),        5.18 (s,2H); 7.40 (s, 5H).

Step-3 (+)-4-Amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine

-   -   4-Amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine (200 g, 0.76        mol) was dissolved in 2.4 L 2-3% aqueous ethyl alcohol (moisture        content 2.6% by Karl Fischer titration) and L-(+)-tartaric acid        (110 g, 0.73 mol) was added to the solution at 65-70° C. The        reaction mixture was heated under stirring for half an hour at        65-70° C. The reaction mixture was cooled under stirring between        20-30° C. The solid was filtered and the wet cake was washed        with additional 675 ml ethyl alcohol.    -   Resultant ‘solid A’ was treated separately to obtain (−) isomer        of 4-amino-1-benzyloxycarbonyl-3,3-dimethyl-piperidine as        described in Step-4.    -   The filtrate was concentrated under vacuum to obtain a ‘solid        B’. The ‘solid B’ was treated with aqueous K₂CO₃ solution made        by dissolving 112 g K₂CO₃ in 1.2 L water and was extracted with        750 ml chloroform thrice. Combined organic extract was washed        with 200 ml water and dried over sodium sulfate. Evaporation of        organic solvent afforded 71 g (71% ) as an oil. The compound was        subjected to a second resolution by dissolving it (70 g, 0.267        mol} in 840 ml 2-3% aqueous ethyl alcohol (moisture content,        2.6%) under stirring and resultant solution was treated with (40        g, 0.267 mol) D-(−)-tartaric acid at 60-70° C. The reaction        mixture was agitated at 65-70° C. for half an hour. The reaction        mass was cooled and was filtered at 20-30° C. The wet cake was        washed with 210 ml additional ethyl alcohol to afford a        crystalline salt. The resultant wet solid was treated with        aqueous K₂CO₃ solution made by dissolving 81 g K₂CO₃ in 0.81 L        water and was extracted with 750 ml×3 chloroform. Combine        organic extract was washed with 200 ml water and was dried over        sodium sulfate. Evaporation of organic solvent afforded 57 g        (86%) as an oil.    -   m/z (M+1) 263.    -   NMR(CDCl₃) D₂O exchange: 0.80 (s, 3H); 0.98 (s, 3H); 1.40-1.78        (m, 2H); 2.50 (dt, 2H); 2.90 (m, 1H); 3.80 (t,1H); 4.18 (t, 1H),        5.18 (s,2H); 7.40 (s, 5H).    -   [α]_(D) ²⁵ value +30.60 (c=1, CHCl₃), percentage of isomers        ratio 98.07:1.93 determined by HPLC of Mosher amide analogue.    -   The process of the resolution is further repeated on the free        base till the unwanted chiral isomer falls below 0.5% limit by        HPLC analysis.

Step-4 (−)-4-Amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine

-   -   The ‘solid A’ obtained in Step-3 was treated with aqueous K₂CO₃        solution made by dissolving 164 g K₂CO₃ in 1.6 L water and was        extracted with 750 ml chloroform thrice. Combined organic        extract was washed with 200 ml water and dried over sodium        sulfate. Evaporation of organic solvent afforded 85 g (85%) as        an oil.    -   The compound was subjected to a second resolution by dissolving        it (84 g, 0.32 mol} in 1.0 L 2-3% aqueous ethyl alcohol        (moisture content, 2.6%) under stirring and resultant solution        was treated with L-(+)-tartaric acid (46 g, 0.307 mol) at        60-70° C. The reaction mixture was agitated at 65-70° C. for        half an hour. The reaction mass was cooled and was filtered at        20-30° C. The wet cake was washed with 250 ml additional ethyl        alcohol to afford a crystalline salt. The resultant white solid        was treated with aqueous K₂CO₃ solution made by dissolving 93 g        K₂CO₃ in 1.0 L water and was extracted with 750 ml×3 chloroform.        Combined organic extract was washed with 200 ml water and was        dried over sodium sulfate. Evaporation of organic solvent        afforded 71 g (83%) as an oil.    -   [α]_(D) ²⁵ value −31.80° (c=1, CHCl₃), percentage of isomers        ratio 96.37:3.63 determined by HPLC of Mosher amide analogue.    -   The process of the resolution is further repeated on the free        base till the unwanted chiral isomer falls below 0.5% limit by        HPLC analysis.

Step-5(+)-1-Benzyloxycarbonyl-4-^(t-)butyloxycarbonylamino-3,3-dimethylpiperidine

-   -   To a solution of        (+)-4-amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine (55 g,        0.209 mol) was dissolved in 500 L dichloromethane was added        triethylamine (22.2 g, 0.209 mol) followed by di-^(t-)butyl        carbonate (45.8 g, 0.209 mol) dissolved in 200 ml        dichloromethane while maintaining temperature between 5-10° C.,        under stirring. The reaction was maintained at 25-35° C. After        completion of reaction the reaction mixture was diluted with 1.0        L water and layers were separated. Combined organic extract was        dried over sodium sulfate and was evaporated to dryness to        obtain 76 g of product.    -   m/z (M+1) 363.    -   NMR(CDCl₃) D₂O exchange: 0.80 (s, 3H); 0.98 (s, 3H); 1.45 (s,        9H); 1.70 (m, 1H); 2.70 (m, 1H); 2.90 (t,1H); 3.40 (t, 1H), 3.80        (t,1H); 4.18 (t, 1H); 4.4 (d,1H), 5.1 (s, 2H); 7.40 (s,5H).    -   [α]^(D) ²⁵ value +16.28° (c=1, CHCl₃).

Step-6(−)-1-Benzyloxycarbonyl-4-^(t-)butyloxycarbonylamino-3,3-dimethylpiperidine

-   -   The compound was prepared as per procedure described for its (+)        isomer in quantitative yield.    -   [α]_(D) ²⁵ value −15.86° (c=1, CHCl₃).

Step-7 (+)-4-^(t)-Butyloxycarbonylamino-3,3-dimethylpiperidine

-   -   (+)-1-Benzyloxycarbonyl-4-^(t-)butyloxycarbonylamino-3,3-dimethylpiperidine        (75 g, 0.207 mol) was dissolved in 500 ml methanol and the        solution was transferred to a Parr reactor. Wet 10% palladium on        carbon (7.5 g) was added to the solution and was stirred at 200        psi hydrogen pressure. Reaction progress was monitored on TLC        and reaction was completed in 3-4 hrs. The reaction mixture was        filtered as soon as it was completed. The residue was washed        with 100 ml methanol. Filtrate was evaporated to dryness to        afford the required product (47 g) in quantitative yield.    -   m/z (M+1) 229.    -   NMR(CDCl₃): 0.95 (bs, 6H); 1.45-1.6 (m, 10H); 1.6-1.8 (m, 1H);        2.4 (d, 1H); 2.5-2.7 (m, 2H); 3.05 (m,1H); 3.3-3.5 (m, 1H), 4.4        (m,1H).

Step-8 (−)-4-^(t)-Butyloxycarbonylamino-3,3-dimethylpiperidine

-   -   The compound was prepared as per procedure described for its (+)        isomer.    -   m/z (M+1) 229.    -   NMR(CDCl₃): 0.95 (bs, 6H); 1.45-1.6 (m, 10 H); 1.6-1.8 (m, 1H);        2.4 (d, 1H); 2.5-2.7 (m, 2H); 3.05 (m,1H); 3.3-3.5 (m, 1H), 4.4        (m, 1H).

Preparation 20 4-Amino-3-ethyl-3-methylpiperidine

-   -   Ammonium acetate (2.5 g, 32.46 mmol) was added to the stirred        solution of 1-benzyl-3-ethyl-3-methyl-4-piperidinone (0.9 g, 3.9        mmol) in methanol (20 ml) and stirring was continued for 3 hr at        ambient temperature. The resulting mixture was cooled at 0° C.        and sodium cyanoborohydride (0.2 g, 3.1 mmol) was added to it.        Cooling was removed after 10 min. and resulting mixture was        stirred for 6 hr at ambient temperature. The reaction mixture        was concentrated to dryness, triturated with water, acidified        with conc. HCl (pH 3˜4) and extracted with ethyl acetate to        remove impurities. The aqueous layer was basified with 1 M        sodium hydroxide solution (pH˜10) and extracted with ethyl        acetate. Ethyl acetate extract was dried (Na₂SO₄) and        concentrated to dryness to furnish        4-amino-1-benzyl-3-ethyl-3-methylpiperidine. Yield 0.6 g (66%),        C₁₅H₂₄N₂, m/z 233 (M+1).    -   A mixture of 20% Pd(OH)₂ on carbon (0.2 g) and        4-amino-1-benzyl-3-ethyl-3-methylpiperidine (0.6 g, 2.58 mmol)        in methanol (210 ml) was stirred in hydrogen atmosphere (1 atm.)        at 30° C. for 6 hr. The catalyst was filtered off, washed with        methanol and filtrate was concentrated to dryness to afford        4-amino-3-ethyl-3-methylpiperidine. Yield 0.27 g (74%), C₈H₁₈N₂,        m/z 143 (M+1).

Preparation 21 4-Methylamino-3-ethyl-3-methylpiperidine

-   -   Potassium hydroxide (15.45 g, 276 mmol) was added to the stirred        solution of methylamine hydrochloride (18.54 g, 276 mmol) in        methanol (100 ml) and stirring was continued for 30 min at        30° C. 1-benzyl-3-ethyl-3-methyl-4-piperidinone (8 g, 34.6 mmol)        was added to the resulting mixture and stirred for 6 hr. Sodium        cyanoborohydride (2.18 g, 34.6 mmol) was added to it and        reaction mixture was stirred for 15 hr. The reaction mixture was        concentrated to dryness, triturated with water, extracted with        chloroform, dried (Na₂SO₄) and concentrated to give        1-benzyl-4-methylamino-3-ethyl-3-methylpiperidine. Yield 6 g        (67%), C₁₆H₂₆N₂, m/z 247 (M+1).    -   A mixture of 20% Pd(OH)₂ on carbon (0.7 g) and        1-benzyl-4-methylamino-3-ethyl-3-methyl piperidine (6 g, 24.39        mmol) in methanol (60 ml) was stirred in hydrogen atmosphere (1        atm.) at 60° C. for 6 hr. The catalyst was filtered off, washed        with methanol and filtrate was concentrated to dryness to afford        4-methylamino-3-ethyl-3-methylpiperidine. Yield 2.5 g (66%),        C₉H₂₀N₂, m/z 157 (M+1).

Preparation 22 4-Cyclopropylamino-3-ethyl-3-methylpiperidine

-   -   1-Benzyl-3-ethyl-3-methyl-4-piperidinone (4.2 g, 18.18 mmol) was        added to the stirred solution cyclopropylamine (6.5 g, 115 mmol)        in methanol (100 ml) and stirred for 6 hr. Sodium        cyanoborohydride (1.14 g, 18.18 mmol) was added to it and        reaction mixture was stirred for 15 hr. The reaction mixture was        concentrated to dryness, triturated with water, extracted with        chloroform, dried (Na₂SO₄) and concentrated to furnish crude        1-benzyl-4-cyclopropylamino-3-ethyl-3-methylpiperidine. Yield 4        g (88%), C₁₈H₂₈N₂, m/z 273 (M+1).    -   A mixture of 20% Pd(OH)₂ on carbon (0.5 g) and        1-benzyl-4-cyclopropylamino-3-ethyl-3-methylpiperidine (3.54 g,        13.00 mmol) in methanol (70 ml) was stirred in hydrogen        atmosphere (1 atm.) at 60° C. for 48 hr. The catalyst was        filtered off, washed with methanol and filtrate was concentrated        to dryness to afford        4-cyclopropylamino-3-ethyl-3-methylpiperidine. Yield 2.3 g        (93%), C₁₁H₂₂N₂, m/z 183 (M+1).

Preparation 23 4-Dimethylamino-3-Ethyl-3-Methylpiperidine

-   -   Paraformaldehyde (10 g) was added to the stirred solution of        4-amino-1-benzyl-3-ethyl-3-methylpiperidine (8.0 g, 34 mmol) in        methanol (100 ml) at 0° C. and sodium cyanoborohydride (2.14 g,        34 mmol) was added to it. Then, acetic acid (2 ml) was added to        the resulting mixture and stirring was continued for 24 hr at        ambient temperature. The reaction mixture was concentrated to        dryness, triturated with water, acidified with conc. HCl (pH        3˜4) and extracted with ethyl acetate to remove impurities. The        aqueous layer was basified with 1 M sodium hydroxide solution        (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract        was dried (Na₂SO₄) and concentrated to give        1-benzyl-4-dimethylamino-3-ethyl-3-methylpiperidine. Yield 6 g        (67%), C₁₇H₂₈N₂, m/z 261 (M+1).    -   A mixture of 20% Pd(OH)₂ on carbon (0.7 g) and        1-benzyl-4-dimethylamino-3-ethyl-3-methyl piperidine (6 g, 23        mmol) in methanol (50 ml) was stirred in hydrogen atmosphere (1        atm.) for 48 hr at room temperature. The catalyst was filtered        off, washed with methanol and filtrate was concentrated to        afford 4-dimethylamino-3-ethyl-3-methylpiperidine. Yield 2.8 g        (72%), C₁₀H₂₂N₂, m/z 171 (M+1).

Preparation 24 4-Amino-3,3-diethylpiperidine

-   -   Ammonium acetate (7.85 g, 102 mmol) was added to the stirred        solution of 1-benzyl-3,3-diethyl piperidin-4-one (5.0 g, 20.40        mmol) in methanol (100 ml) and stirring was continued for 3 hr        at ambient temperature. The resulting mixture was cooled at        0° C. and sodium cyanoborohydride (1.3 g, 20.40 mmol) was added        to it. Cooling was removed after 10 min. and resulting mixture        was stirred for 6 hr at ambient temperature. The reaction        mixture was concentrated to dryness, triturated with water,        acidified with conc. HCl (pH 3˜4) and extracted with ethyl        acetate to remove impurities. The aqueous layer was basified        with 1 M sodium hydroxide solution (pH˜10) and extracted with        ethyl acetate. Ethyl acetate extract was dried (Na₂SO₄) and        concentrated to dryness to furnish 4-amino-1-benzyl-3,3-diethyl        piperidine. Yield 8.2 g (82%), C₁₆H₂₆N₂, m/z 247 (M+1), PMR        (CDCl₃): 0.84 (s, 3H), 0.98 (s, 3H), 1.48 (bs, 2H, D₂O        exchangeable), 1.66 (m, 2H), 2.04 (m, 2H), 2.42 (m, 2H), 2.86        (m, 1H), 3.46 (dd, 2H), 7.32 (m, 5H).    -   A mixture of 20% Pd(OH)₂ on carbon (0.8 g) and        4-amino-1-benzyl-3,3-diethylpiperidine (8.0 g, 32.52 mmol) in        methanol (100 ml) was stirred in hydrogen atmosphere (1 atm.) at        30° C. for 6 hr. The catalyst was filtered off, washed with        methanol and filtrate was concentrated to dryness to afford        4-amino-3,3-diethylpiperidine. Yield 4.8 g (94.60%), C₉H₂₀N₂,        m/z 157 (M+1), PMR (CDCl₃): 0.9 (s, 6H), 1.5 (m, 2H), 1.58 (bs,        2H, D₂O exchangeable), 2.26-2.68 (m, 4H), 3.06 (m, 1H), 3.52        (bs, 1H, D₂O exchangeable).

Preparation 25 4-Amino-3,5-dimethylpiperidine Step-1 Mixture of Isomersof 4-amino-1-carbethoxy-3,5-dimethylpiperidine

-   -   Ethyl chloroformate (10.0 g, 90 mmol) was added to a stirred        solution of 1-benzyl-3,5-dimethyl-4-piperidinone (5.0 g, 24        mmol) in benzene (20 ml), refluxed with stirring for 6 hr and        concentrated to dryness to give        1-carbethoxy-3,5-dimethyl-4-piperidinone as oil. Yield 4.51 g        (90%), C₁₀H₁₇NO₃, m/z 200 (M+1).    -   Ammonium acetate (20 g) was added to the stirred solution of        1-carbethoxy-3,5-dimethyl-4-piperidinone (4.5 g, 22.5 mmol) in        methanol (200 ml) and stirred for 3 hr. The resulting mixture        was cooled at 0° C. and sodium cyanoborohydride (1.4 g, 22.5        mmol) was added to it. Cooling was removed and stirring was for        3 hr at 35° C. The reaction mixture was concentrated, triturated        with water, acidified with conc. HCl (pH 3˜4) and extracted with        ethyl acetate to remove impurities. The aqueous layer was        basified with 1 M sodium hydroxide solution (pH˜10) and        extracted with ethyl acetate. Ethyl acetate extract was dried        (Na₂SO₄) and concentrated to give        4-amino-1-carbethoxy-3,5-dimethylpiperidine. The obtained        4-amino-1-carbethoxy-3,5-dimethylpiperidine was subjected to        silica gel column chromatography. Elution with 5% methanol in        chloroform furnished a solid, which was a mixture of        stereoisomers, conformational analysis of which was not        obtained.    -   Yield 3.5 g (77%), m.p. 218-20° C., C₁₀H₁₈N₂O₂, m/z 201 (M+1).

Step-2 Separation of Isomers of4-amino-1-carbethoxy-3,5-dimethylpiperidine

-   -   4-Amino-1-carbethoxy-3,5-dimethylpiperidine obtained as per        procedure described in Step-1 was subjected to silica gel column        chromatography. Elution with chloroform gave “upper” mixture of        isomers of 4-amino-1-carbethoxy-3,5-dimethylpiperidine m.p.        248-50° C., C₁₀H₁₈N₂O₂, m/z 201 (M+1), PMR (CDCl₃): 0.94 (m,        6H), 1.16 (t, 3H), 1.78 (m, 1H), 2.02 (m, 1H), 2.06 (bs, 2H, D₂O        exchangeable), 2.72 (m, 2H), 2.86 (m, 1H), 3.74 (m, 2H), 4.12        (q, 2H).    -   Further elution with 5% methanol in chloroform furnished “lower”        mixture of isomers of        4-amino-1-carbethoxy-3,5-dimethylpiperidine m.p. 236-40° C.,        C₁₀H₁₈N₂O₂, m/z 201 (M+1), PMR (CD₃OD): 0.88 (m, 6H), 1.16 (t,        3H), 1.82 (m, 1H), 2.1 (m, 1H), 2.5 (m, 2H), 2.94-3.15 (m, 3H),        3.96 (q, 2H).

Step-3 Mixture of Isomers of 4-amino-3,5-dimethylpiperidine (MixturesA+B)

-   -   A mixture of isomers of        4-amino-1-carbethoxy-3,5-dimethylpiperidine (10 g, 51 mmol)        obtained by a procedure as described in step-1, was stirred in 5        M NaOH solution (100 ml) at 100° C. for 48 hr, cooled, extracted        with ethyl acetate, dried (Na₂SO₄) and concentrated to afford        mixture of isomers of 4-amino-3,5-dimethylpiperidine as oil as        “mixture A+B”. Yield 5.1 g (80%), C₇H₁₆N₂, m/z 129 (M+1).

Step-4 “Upper” Mixture of Isomers of 4-amino-3,5-dimethylpiperidine(Mixture A of Isomers)

-   -   A “upper” mixture of isomers of        4-amino-1-carbethoxy-3,5-dimethylpiperidine (1.5 g, 7.5 mmol)        obtained as described in Step-2, was stirred in 5 M NaOH        solution (10 ml) at 100° C. for 48 hr, cooled, extracted with        ethyl acetate, dried (Na₂SO₄) and concentrated to afford “upper”        mixture of isomers of 4-amino-3,5-dimethyl piperidine as oil as        mixture A of isomers, of which the conformational analysis was        not obtained. Yield 0.72 g (76%), C₇H₁₆N₂, m/z 129 (M+1), PMR        (CDCl₃): 0.94 (m, 6H), 1.7 (bs, 3H, D₂O exchangeable), 1.78 (m,        1H), 2.02 (m, 1H), 2.5-2.8 (m, 4H), 2.86 (m,1H).

Step-5 “Lower” Mixture of Isomers of 4-amino-3,5-dimethylpiperidine(Mixture B of Isomers)

-   -   A “lower” mixture of isomers of        4-amino-1-carbethoxy-3,5-dimethylpiperidine (1.0 g, 5.0 mmol)        obtained by a procedure as described in step-2, was stirred in 5        M NaOH solution (10 ml) at 100° C. for 48 hr, cooled, extracted        with ethyl acetate, dried (Na₂SO₄) and concentrated to afford        “lower” mixture of isomers of 4-amino-3,5-dimethylpiperidine as        an oil as mixture B of isomers, of which the conformational        analysis was not obtained. Yield 0.51 g (80%), C₇H₁₆N₂, m/z 129        (M+1).

Preparation 26 4-Methylamino-3,5-Dimethylpiperidine

-   -   Powdered KOH (0.92 g, 16.44 mmol) was added in portions to the        stirred solution of methylamine hydrochloride (1.11 g, 16.44        mmol) in methanol (20 ml) at 0-5° C. and        1-carbethoxy-3,5-dimethyl-4-piperidinone (2.2 g, 1.1 mmol),        obtained by a procedure as described in Example 25 (Step-1), was        added in portions to it. The resulting reaction mixture was        stirred for 45 min at 10° C. and a solution of sodium        cyanoboro-hydride (0.7 g, 1.1 mmol) in methanol (5 ml) was added        dropwise to it. Cooling was removed and stirring was for 24 hr        at 30° C. The reaction mixture was basified with 20% KOH        solution, filtered (to remove insoluble impurities) and filtrate        was concentrated to dryness. The obtained residue was dissolved        in water and extracted with chloroform. Chloroform layer was        extracted with 50% HCl and acid layer was basified with 20% KOH        solution. The separated oil was extracted with chloroform, dried        (Na₂SO₄) and concentrated to give a Mixtures A+B of        4-methylamino-1-carbethoxy-3,5-dimethylpiperidine. Yield 1.34 g        (60%), C₁₁H₂₂N₂O₂, m/z 214 (M+1).    -   Mixtures A+B of        4-methylamino-1-carbethoxy-3,5-dimethylpiperidine (1.3 g, 0.6        mmol) was stirred in a mixture of 10% NaOH solution (20 ml) and        ethyl alcohol (10 ml) at 100° C. for 120 hr, cooled, extracted        with ethyl acetate, dried (Na₂SO₄) and concentrated to afford a        Mixtures A+B of 4-methylamino-3,5-dimethylpiperidine. Yield 0.61        g (70%), C₈H₁₈N₂, m/z 143 (M+1).    -   Mixture A of isomers and Mixture B of isomers of        4-methylamino-3,5-dimethylpiperidine were prepared by separation        technique at 4-methylamino-1-carbethoxy-3,5-dimethylpiperidine        stage by using silica gel column chromatography similar as        described in Preparation 25 (Step-2) followed by aqueous sodium        hydroxide mediated hydrolysis.

Preparation 27 4-Ethylamino-3,5-dimethylpiperidine

-   -   Powdered KOH (2.8 g, 50 mmol) was added in portions to the        stirred solution of ethylamine hydrochloride (4.0 g, 50 mmol) in        methanol (50 ml) and 1-carbethoxy-3,5-dimethyl-4-piperidinone        (5.0 g, 25.12 mmol) obtained by a procedure as described in        Example 25 (Step-1), was added to it. The resulting reaction        mixture was stirred for 6 hr. A solution of sodium        cyanoborohydride (1.6 g, 25.12 mmol) in methanol (10 ml) was        added dropwise to it and stirring was continued for 16 hr. The        reaction mixture was concentrated to dryness. The obtained        residue was dissolved in water and extracted with chloroform.        Chloroform layer was extracted with 50% HCl and acid layer was        basified with KOH (20%) solution. The oil thus separated was        extracted with chloroform, dried (Na₂SO₄) and concentrated to        give Mixtures A+B of        4-ethylamino-1-carbethoxy-3,5-dimethylpiperidine as an oil.        Yield 5.6 g (97.7%), C₁₂H₂₄N₂O₂, m/z 229 (M+1).    -   The similarly obtained Mixtures A+B of        4-ethylamino-1-carbethoxy-3,5-dimethylpiperidine was separated        over silica gel column chromatography. Elution from 5% methanol        in chloroform gave Mixture A of isomers of        4-ethylamino-1-carbethoxy-3,5-dimethylpiperidine as oil. Yield        2.1 g (36%), C₁₂H₂₄N₂O₂, m/z 229 (M+1), PMR (CDCl₃): 0.94 (dd,        6H), 1.25 (t, 3H), 1.5-2.1 (3H, m, D₂O exchangeable), 2.38 (m,        1H), 2.72 (m, 2H), 3.3-3.8 (m, 3H), 3.64 (s, 1H), 4.12 (q, 2H).        Further elution from 5% methanol in chloroform furnished Mixture        B of isomers of 4-ethylamino-1-carbethoxy-3,5-dimethylpiperidine        as oil. Yield 2.1 g (36%), C₁₂H₂₄N₂O₂, m/z 229 (M+1), PMR        (CDCl₃): 0.92 (dd, 6H), 1.18 (t, 3H), 1.48 (bs, 1H, D₂O        exchangeable), 1.68 (m, 1H), 2.02 (m, 1H), 2.3 (m, 1H), 2.4-2.68        (m, 3H), 3.0 (dd, 1H), 3.82 (dd, 1H), 3.95 (m, 1H), 4.12 (m,        2H).    -   The Mixture A of isomers of        4-ethylamino-1-carbethoxy-3,5-dimethylpiperidine (2.1 g, 0.92        mmol) was stirred in 5 N NaOH solution (20 ml) at 100° C. for 96        hr, cooled, extracted with ethyl acetate, dried (Na₂SO₄) and        concentrated to afford Mixture A of isomers of        4-ethylamino-3,5-dimethyl piperidine as oil. Yield 1.34 g        (93.2%), C₉H₂₀N₂, m/z 157 (M+1), PMR (CDCl₃): 0.94 (dd, 9H),        1.45 (m, 1H), 1.66 (m, 1H), 1.94 (m, 3H, D₂O exchangeable), 2.36        (m, 1H), 2.44-2.74 (m, 3H), 3.0 (dd, 1H), 3.5 (m, 1H).    -   The Mixture B of isomers of        4-ethylamino-1-carbethoxy-3,5-dimethylpiperidine (2.1 g, 0.92        mmol) was stirred in 5 N NaOH solution (20 ml) at 100° C. for 96        hr, cooled, extracted with ethyl acetate, dried (Na₂SO₄) and        concentrated to afford Mixture B of isomers        4-ethylamino-3,5-dimethylpiperidine as oil. Yield 1.34 g        (93.2%), C₉H₂₀N₂, m/z 157 (M+1), PMR (CDCl₃): 0.94 (dd, 6H),        1.12 (t, 3H), 1.5-1.8 (m, 3H, D₂O exchangeable), 1.9 (m, 1H),        2.28 (m, 2H), 2.46 (m, 1H), 2.62-3.0 (m, 4H).

Preparation 28 4-Cyclopropylamino-3,5-dimethylpiperidine

-   -   A solution of cyclopropylamine (71.6 g, 126 mmol) and        1-carbethoxy-3,5-dimethyl-4-piperidinone (50 g, 26 mmol)        obtained by a procedure as described in Example 25 (Step-1), in        methanol (500 ml) was stirred for 6 hr at ambient temperature.        Sodium cyanoborohydride (16 g, 26 mmol) was added in portions to        the resulting mixture and stirring was continued for 16 hr. The        reaction mixture was concentrated to dryness. The obtained        residue was dissolved in water and extracted with chloroform.        Chloroform layer was extracted with 6N HCl and HCl extract was        basified with aqueous KOH (20%) solution. The oil thus separated        was extracted with chloroform, dried (Na₂SO₄) and concentrated        to give a mixture of Mixtures A+B of        1-carbethoxy-4-cyclopropylamino-3,5-dimethylpiperidine as oil.        Yield 58 g (96%), C₁₃H₂₄N₂O₂, m/z 241 (M+1).    -   The similarly obtained Mixture A+B of        1-carbethoxy-4-cyclopropylamino-3,5-dimethylpiperidine was        separated over silica gel column chromatography. Elute from 5%        ethyl acetate in hexane gave Mixture A of isomers of        1-carbethoxy-4-cyclopropyamino-3,5-dimethylpiperidine as oil.        C₁₃H₂₄N₂O₂, m/z 241 (M+1), PMR (CDCl₃): 0.88-1.17 (m, 10H), 1.3        (t, 3H), 1.74 (bs, 1H, D₂O exchangeable), 2.48-2.82 (m, 4H),        3.26-3.85 (m, 2H), 4.18 (q, 2H), 4.42 (bm, 2H),    -   Further elution from 5% ethyl acetate in hexane furnished        Mixture B of isomers of        1-carbethoxy-4-cyclopropylamino-3,5-dimethylpiperidine as oil.        C₁₃H₂₄N₂O₂, m/z 241 (M+1), PMR (CDCl₃): 0.78-1.08 (m, 10H), 1.15        (t, 3H), 1.48-2.1 (m, 4H, D₂O exchangeable), 2.32-2.82 (m, 2H),        3.24-3.82 (m, 2H), 4.04-4.25 (m, 3H).    -   Mixture A of isomers of        1-carbethoxy-4-cyclopropylamino-3,5-dimethylpiperidine (3.5 g,        1.45 mmol) was stirred in 5 N NaOH solution (25 ml) at 100° C.        for hr, cooled, extracted with ethyl acetate, dried (Na₂SO₄) and        concentrated to afford Mixture A of isomers of        4-cyclopropylamino-3,5-dimethyl piperidine as oil. Yield 2.1 g        (85%), C₁₀H₂₀N₂, m/z 169 (M+1).    -   The Mixture B of isomers of        1-carbethoxy-4-cyclopropylamino-3,5-dimethylpiperidine (2.8 g,        1.16 mmol) was stirred in a mixture 5 N NaOH solution (20 ml)        and ethyl alcohol (5 ml) at 100° C. for 120 hr, cooled,        extracted with ethyl acetate, dried (Na₂SO₄) and concentrated to        afford Mixture B of isomers of        4-cyclopropylamino-3,5-dimethylpiperidine as an oil. Yield 1.6 g        (84%), C₁₀H₂₀N₂, m/z 169 (M+1) PMR (CDCl₃): 0.82-1.05 (m, 10H),        1.5 (m, H), 1.75 (m, H,), 2.16-2.38 (m, 3H), 2.65 (m, 1H), 2.78        (m, 1H), 3.02 (m, 1H), 3.41 (m, 1H), 3.64 (m, 1H).

Preparation 29 4-Dimethylamino-3,5-dimethylpiperidine

-   -   Potassium hydroxide (3.86 g) was added to the stirred solution        of N,N-dimethylamine hydrochloride (5.63 g, 69.0 mmol) in        methanol (20 ml) and stirring was continued for 30 min at 30° C.        1-benzyl-3,5-methyl-4-piperidinone (3 g, 13.8 mmol) was added to        the stirred mixture and refluxed for 48 hr. Reaction mixture was        cooled at 30° C. and sodium cyanoborohydride (0.87 g, 13.8 mmol)        was added. The resulting reaction mixture was stirred for 24 hr        at 70° C. The reaction mixture was concentrated to dryness,        triturated with water, extracted with chloroform, dried (Na₂SO₄)        and concentrated to give Mixtures A+B of        1-benzyl-4-dimethylamino-3,5-dimethylpiperidine. Yield 2.7 g        (79.4%), C₁₆H₂₆N₂, m/z 247 (M+1).    -   A mixture of 20% Pd(OH2 on carbon (0.5 g) and Mixtures A+B of        1-benzyl-4-dimethylamino-3,5-dimethylpiperidine (2.7 g, 10.1        mmol) in methanol (50 ml) was stirred in hydrogen atmosphere (1        atm.) at 60° C. for 48 hr. The catalyst was filtered off, washed        with methanol and filtrate was concentrated to dryness to afford        Mixtures A+B of 4-dimethylamino-3,5-dimethylpiperidine. Yield        0.9 g (52.6%), C₉H₂₀N₂, m/z 157 (M+1).    -   Mixture A of isomers and Mixture B of isomers of        4-dimethylamino-3,5-dimethylpiperidine were prepared by        separation technique at        1-benzyl-4-dimethylamino-3,5-dimethylpiperidine stage by using        silica gel column chromatography followed by debenzylation by        using catalytic palladium hydroxide on carbon.

Preparation 30 4-Amino-3,5-diethylpiperidine

-   -   Ammonium acetate (10 g, 130 mmol) was added to the stirred        solution of 1-benzyl-3,5-diethyl-4-piperidone (3.5 g, 14.3 mmol)        in methanol (50 ml) and stirring was continued for 4 hr at        ambient temperature. The resulting mixture was cooled at 0° C.        and sodium cyanoborohydride (0.45 g, 7.14 mmol) was added to it.        Cooling was removed after 10 min. and resulting mixture was        stirred for 10 hr at ambient temperature. The reaction mixture        was concentrated to dryness, triturated with water, acidified        with conc. HCl (pH 2) and extracted with ethyl acetate to remove        impurities. The aqueous layer was basified with 1 M sodium        hydroxide solution (pH 10) and extracted with ethyl acetate.        Ethyl acetate extract was dried (Na₂SO₄) and concentrated to        dryness to furnish 4-amino-1-benzyl-3,5-diethylpiperidine. Yield        3.4 g (97%), C₁₆H₂₆N₂, m/z 247 (M+1).    -   A mixture of 5% Pd on carbon (0.5 g) and        4-amino-1-benzyl-3,5-diethylpiperidine (3.4 g, 13.82 mmol) in        methanol (25 ml) was stirred in hydrogen atmosphere (3 atm.) at        60° C. for 6 hr. The catalyst was filtered off, washed with        methanol and filtrate was concentrated to dryness to afford        4-amino-3,5-diethylpiperidine as an oil. Yield 1.4 g (64.5%),        C₉H₂₀N₂, m/z 157 (M+1).

Preparation 31 4-Amino-3,3,5-trimethylpiperidine

-   -   A mixture of 20% Pd(OH)₂ on carbon (0.3 g) and        1-benzyl-3,3,5-trimethyl-4-piperidone (1.5 g, 6.5 mmol) in        methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) at        30° C. for 6 hr. The catalyst was filtered off, washed with        methanol and filtrate was concentrated to dryness to afford        3,3,5-trimethyl-4-piperidinone. Yield 0.8 g (88%), C₈H₁₅NO, m/z        142 (M+1).    -   Ammonium acetate (2.5 g, 32.46 mmol) was added to the stirred        solution of 3,3,5-trimethyl-4-piperidone (0.8 g, 5.67 mmol) in        methanol (20 ml) and stirring was continued for 3 hr at ambient        temperature. The resulting mixture was cooled at 0° C. and        sodium cyanoborohydride (0.25 g, 3.96 mmol) was added to it.        Cooling was removed after 10 min. and resulting mixture was        stirred for 6 hr at ambient temperature. The reaction mixture        was concentrated to dryness, triturated with water, acidified        with conc. HCl (pH 3˜4) and extracted with ethyl acetate to        remove impurities. The aqueous layer was basified with 1 M        sodium hydroxide solution (pH˜10) and extracted with ethyl        acetate. Ethyl acetate extract was dried (Na₂SO₄) and        concentrated to dryness to furnish        4-amino-3,3,5-trimethylpiperidine. Yield 0.45 g (54%), C₈H₁₈N₂,        m/z 143 (M+1).

Preparation 32 4-Amino-3,5-diethyl-3-methylpiperidine

-   -   Ammonium acetate (8.0 g, 104 mmol) was added to the stirred        solution of 1-benzyl-3,5-diethyl-3-methyl-4-piperidone (2.5 g,        9.65 mmol) in methanol (25 ml) and stirring was continued for 24        hr at ambient temperature. The resulting mixture was cooled at        0° C. and sodium cyanoborohydride (0.69 g, 11.2 mmol) was added        to it. Cooling was removed after 10 min. and resulting mixture        was stirred for 20 hr at ambient temperature. The reaction        mixture was concentrated to dryness, triturated with water,        acidified with conc. HCl (pH 2) and extracted with ethyl acetate        to remove impurities. The aqueous layer was basified with 1M        sodium hydroxide solution (pH 9) and extracted with ethyl        acetate. Ethyl acetate extract was dried (Na₂SO₄) and        concentrated to dryness to furnish        4-amino-1-benzyl-3,5-diethyl-3-methylpiperidine as an oil. Yield        2.1 g (84%), C₁₇H₂₈N₂, m/z 261 (M+1).    -   A mixture of 20% Pd(OH)₂ on carbon (0.3 g) and        4-amino-1-benzyl-3,5-diethyl-3-methylpiperidine (2.1 g, 8.07        mmol) in methanol (50 ml) was stirred in hydrogen atmosphere (4        atm.) at 45° C. for 4 hr. The catalyst was filtered off, washed        with methanol and filtrate was concentrated to dryness to afford        4-amino-3,5-diethyl-3-methyl-piperidine as an oil. Yield 1.2 g        (88%), C₁₀H₂₂N₂, m/z 171 (M+1).

Preparation 33 4-Amino-3,5-dimethyl-3-ethylpiperidine

-   -   Ammonium acetate (2.5 g, 32.46 mmol) was added to the stirred        solution of 1-benzyl-3,5-dimethyl-3-ethyl-4-piperidone (3.0 g,        12.25 mmol) in methanol (40 ml) and stirring was continued for        20 hr at ambient temperature. The resulting mixture was cooled        at 0° C. and sodium cyanoborohydride (0.8 g, 12.7 mmol) was        added to it. Cooling was removed after 10 min. and resulting        mixture was stirred for 20 hr at ambient temperature. The        reaction mixture was concentrated to dryness, triturated with        water, acidified with conc. HCl (pH 2) and extracted with ethyl        acetate to remove impurities. The aqueous layer was basified        with 1M sodium hydroxide solution (pH 9) and extracted with        ethyl acetate. Ethyl acetate extract was dried (Na₂SO₄) and        concentrated to dryness to furnish        4-amino-1-benzyl-3,5-dimethyl-3-ethylpiperidine. Yield 2.2 g        (73%), C₁₆H₂₆N₂, m/z 247 (M+1).    -   A mixture of 20% Pd(OH)₂ on carbon (0.4 g) and        4-amino-1-benzyl-3,5-dimethyl-3-ethylpiperidine (2.2 g, 8.9        mmol) in methanol (15 ml) was stirred in hydrogen atmosphere (1        atm.) at 60° C. for 10 hr. The catalyst was filtered off, washed        with methanol and filtrate was concentrated to dryness to afford        4-amino-3,5-dimethyl-3-ethylpiperidine as a semi solid. Yield        1.1 g (79%), C₉H₂₀N₂, m/z 157 (M+1).

Preparation 34 cis ortrans-4-t-Butyloxycarbonylamino-1-benzyl-3-methylpiperidine Step-1Ethyl-1-benzyl-3-methyl-4-oxo-piperidine-3-carboxylate

-   -   Ethyl-1-benzyl-4-oxo-piperidine-3-carboxylate hydrochloride (150        g, 0.504 mol) was suspended in a solvent mixture of 750 ml THF        and 750 ml DMF at room temperature. Addition of powdered KOH (56        g, 1.0 mol) was made in two equal lots keeping half an hour        interval between two additions. To a clear reaction mixture        methyl iodide (78 g, 0.55 mol) was added over period of 10        minutes and it was stirred for three hours at room temperature.        The reaction was quenched by adding 4 ltr water followed by 1.5        ltr diethyl ether. Layers were separated. Organic layer was        washed with water and dried over Na₂SO₄. Evaporation of organic        solvent afforded a liquid, which was passed through a silica gel        column to give 86 g (61%), titled compound.    -   mass (ES⁺) 276, Molecular Formula C₁₆H₂₁NO₃,    -   H¹NMR (CDCl₃) 1.2 (s, 3H), 1.25 (t, 2H), 2.15 (d, 1H), 2.35-2.5        (m, 2H), 2.9 (d, 2H), 3.45 (d, 1H), 3.6 (s, 2H), 4.12-4.3 (m,        2H), 7.3 (s, 5H).

Step-2 1-Benzyl-3-methyl-4-piperidone

-   -   Ethyl-1-benzyl-3-methyl-4-oxo-piperidine-3-carboxylate (85 g,        0.31 mol) was dissolved in conc HCl (82 ml, 0.77 mol) and the        reaction mixture was heated to 100° C. for 32 hrs. Solvent was        removed under reduced pressure and the resulting solid was        dissolved in the 300 ml CHCl3 and 400 ml pet ether was added to        this under stirring to provide a solid. The solid was filter and        was dissolved in 400 ml ethyl acetate and organic layer was        washed with 10% NaOH aqueous solution. Layers were separated and        concentration of organic layer afforded 48 g (75%) oil as a        titled product.    -   mass (ES⁺) 204, Molecular Formula C₁₃H₁₇NO,    -   H¹NMR (CDCl₃) 1.0 (d, 3H), 2.1 (t, 1H), 2.3-2.5 (m, 2H), 2.6-2.8        (m, 2H), 3.0-3.2 (m, 2H), 3.6 (s, 2H), 7.4 (s, 5H).

Step-3 4-Amino-1-benzyl-3-methylpiperidine

-   -   Ammonium acetate (178.3 g, 2.31 mol) was charged to a solution        of 1-benzyl-3-methyl-4-piperidone (47 g, 0.232 mol) in 500 ml        methanol. The suspension was stirred for 4 hours at room        temperature. Sodium cyanoborohydride (7.3 g, 0.116 mol) was        added in lots at 10° C. and it was stirred for 1 hour.    -   Solvent was removed under vacuum and resultant solid was        suspended in 500 ml water and acidified with dilute aqueous HCl.        It was extracted with 200 ml×2 chloroform and layers were        separated. Aqueous layer was basified with ammonia solution to        pH 9 and extracted with 500 ml×3 CHCl₃. Drying of organic layer        over Na₂SO₄ and evaporation afforded 44 g (92%) titled product        as an oil, which was used directly for further reaction.

Step 4 cis ortrans-4-t-Butyloxycarbonylamino-1-benzyl-3-methylpiperidine

-   -   Di-tert-butyloxydicarbonate (45 g, 0.206 mol) was charged in        lots to a solution of 4-amino-1-benzyl-3-methylpiperidine (42 g,        0.206 mol) and 300 ml CH₂Cl₂ followed by 5 ml triethylamine.        Reaction was worked up after 90 minutes by adding 300 ml water        and layers were separated Drying of organic layer over Na₂SO₄        and evaporation yielded mixture of cis and trans isomers in        unequal proportion which when subjected to silica gel column        chromatography with 10% ethyl acetate and hexane yielded 14 g of        cis isomer and 11 g trans isomer and 19 gm mixture of both        isomers of titled compound.    -   For cis isomer:    -   mass (ES⁺) 305, Molecular Formula C₁₈H₂₈N₂O₂,    -   H¹NMR (CDCl₃) 0.95 (d, 3H), 1.45 (s, 9H), 1.7-1.8 (m, 2H),        2.0-2.2 (m, 2H), 2.35-2.5 (m, 2H), 3.5 (d, 2H), 3.7-3.8(bs, 1H),        4.5 (bs, 1H), 7.3 (s, 5H).    -   For trans isomer:    -   mass (ES⁺) 305, Molecular Formula C₁₈H₂₈N₂O₂,    -   H¹NMR (CDCl₃) 0.90 (d, 3H), 1.45 (s, 9H), 1.7-1.8 (t, 2H),        1.9-2.1 (m, 2H), 2.8-2.9 (m, 2H), 3.1 (m, 1H), 3.45(s, 2H), 4.3        (m, 1H), 7.3 (s, 5H).

Preparation 35 cis-4-t-Butyloxycarbonylamino-3-methylpiperidine

-   -   cis-4-t-Butyloxycarbonylamino-1-benzyl-3-methylpiperidine(13 g,        0.042 mol) was dissolved in 170 ml methanol and transferred to        the Parr pressure reactor after addition of 1.3 g of Pd(OH)₂ on        carbon. The rqcytoion mixture stirred for 6 hrs at 400 psi        pressure at 50° C. Catalyst was removed by filtration and        eavaporation of the solvent afforded 8.7 g (95%) of titled        compound.    -   mass (ES⁺) 215, Molecular Formula C₁₁H₂₂N₂O₂,    -   H¹NMR (CDCl₃) 0.90 (d, 3H), 1.45 (s, 9H), 1.7 (m, 2H), 2.0 (m,        2H), 2.8 (m, 2H), 3.8 (bs, 1H), 4.7 (bs, 1H).

Preparation 36 trans-4-t-Butyloxycarbonylamino-3-methylpiperidine

-   -   trans4-t-Butyloxycarbonylamino-3-methylpiperidine was obtained        as per procedure depicted in preparation 000 by using        trans-4-t-Butyloxycarbonylamino-1-benzyl-3-methylpiperidine in        the place of        cis-4-t-Butyloxycarbonylamino-1-benzyl-3-methylpiperidine in 96%        yield.    -   mass (ES⁺) 215, Molecular Formula C₁₁H₂₂N₂O₂,    -   H¹NMR (CDCl₃) 0.90 (d, 3H), 1.40 (s, 9H), 1.9 (m, 2H), 2.8 (m,        2H), 3.1 (m, 2H), 3.4 (s, 1H), 4.3 (m, 1H).

Preparation 37 (−)-4-Amino-3,3-dimethylpiperidine

-   -   A mixture of 10% palladium on carbon (7.5 g) and        (−)-4-amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine (cf.        Preparation 19, Step 4, 50 g, 191.0 mmol) in methanol (500 ml)        was stirred under hydrogen atmosphere (30 atm.) at 30° C. for 6        hr. The catalyst was filtered off, washed with 100 ml methanol        and filtrate was concentrated to dryness to afford        (−)-4-amino-3,3-dimethylpiperidine, which was further purified        by vacuum distillation to give 16.8 (71%) titled compound.    -   C₇H₁₆N₂, m/z 129 (M+1), PMR (CDCl₃): 0.9 (s, 6H), 1.5 (m, 2H),        1.58 (bs, 2H, D₂O exchangeable), 2.26-2.68 (m, 4H), 3.06 (m,        1H), 3.52 (bs, 1 H, D₂O exchangeable). [α]_(D) ²⁵ value −31.72        (c=1, CHCl₃).

Preparation 38 (+)-4-Amino-3,3-dimethylpiperidine

-   -   The titled compound was prepared by the procedure described in        Preparation 37, by using        (+)-4-amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine (cf.        Preparation 19, Step 3, 44 g, 168.0 mmol), to give 15.0 (70%)        titled compound. C₇H₁₆N₂, m/z 129 (M+1), PMR (CDCl₃): 0.9 (s,        6H), 1.5 (m, 2H), 1.58 (bs, 2H, D₂O exchangeable), 2.26-2.68 (m,        4H), 3.06 (m, 1H), 3.52 (bs, 1H, D₂O exchangeable). [α]_(D) ²⁵        value +32.34 (c=1, CHCl₃).

Example 11-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   A mixture of        [1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylate-O³,O⁴]difluoroboron        chelate (0.1 g, 0.29 mmol) and 4-amino-3-methylpiperidine (0.2        g, 1.75 mmol) in acetonitrile (20 ml) was refluxed for 6 hr. The        reaction mixture was concentrated to dryness. The obtained        residue was treated with triethylamine (3 ml) and ethanol        (15 ml) and refluxed for 16 hr. The resulting mixture was        concentrated to dryness; the solid thus obtained was triturated        with water (10 ml), filtered, washed with water, dried and        purified by preparative HPLC to furnish the required product.        Yield 0.04 g (35%), m.p.238-40° C., C₂₀H₂₄FN₃O₄, m/z 390 (M+1),        PMR (CD₃OD): 0.84-1.42 (m, 7H), 1.8-2.4 (m, 3H), 3.02 (m, 1H),        3.18-3.72 (m, 4H), 3.8 (s, 3H), 4.18 (m, 1H), 7.82 (d, 1H), 8.9        (s, 1H).

Example 2trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where trans-4-amino-3-methylpiperidine was used in place of        4-amino-3-methylpiperidine. Yield 35%, m.p.240-42° C.,        C₂₀H₂₄FN₃O₄, m/z 390 (M+1).

Example 3cis-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where cis-4-amino-3-methylpiperidine was used in place of        4-amino-3-methylpiperidine Yield 35%, m.p.246-50° C.,        C₂₀H₂₄N₃O₄F, m/z 390 (M+1).

Example 41-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example        1,where 4-methylamino-3-methylpiperidine was used in place of        4-amino-3-methylpiperidine. Yield 50%, m.p.240° C. (decomp.),        C₂₁H₂₆FN₃O₄, m/z 404 (M+1).

Example 51-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-ethylamino-3-methylpiperidine was used in place of        4-amino-3-methylpiperidine. Yield 52%, m.p. 160-62° C.,        C₂₂H₂₈FN₃O₄, m/z 418 (M+1).

Example 61-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-cyclopropyl amino-3-methylpiperidine was used in place        of 4-amino-3-methylpiperidine. Yield 60%, m.p.182-84° C.,        C₂₃H₂₈FN₃O₄, m/z 430 (M+1).

Example 71-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-dimethyl amino-3-methylpiperidine was used in place of        4-amino-3-methylpiperidine. Yield 74%, m.p.180-82° C.,        C₂₂H₂₈FN₃O₄, m/z 418 (M+1), PMR (CD₃OD): 0.88-1.28 (m, 7H),        1.8-2.3 (m, 3H), 2.92 (s, 6H), 2.66-3.62 (m, 5H), 3.76 (s, 3H),        4.14 (m, 1H), 7.68(d, 1H), 8.78 (s, 1H).

Example 81-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethoxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-1-carbethoxy amino-3,3-dimethyl piperidine was used in        place of 4-amino-3-methyl-piperidine. Yield 16%, m.p.222° C.,        C₂₄H₃₀FN₃O₆, m/z 476 (M+1), PMR (CDCl₃): 1.04 (m, 9H), 1.26 (m,        4H), 1.86 (m, 2H), 3.02-3.68 (m, 4H), 3.72 (s, 3H), 4.02 (m,        1H), 4.16 (q, 2H), 4.58 (m, 1H), 7.86 (d, 1H), 8.82 (s, 1H),        14.8 (s, 1H, D₂O exchangeable).

Example 9(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-benzyloxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-(±)-benzyloxy carbonylamino-3,3-dimethylpiperidine was        used in place of 4-amino-3-methylpiperidine: Yield 47%,        m.p.158-60° C., C₂₉H₃₂FN₃O₆, m/z 538 (M+1), PMR (CDCl₃): 1.0 (s,        6H), 1.26 (m, 4H), 1.84 (m, 2H), 3.04-3.7 (m, 4H), 3.76 (s, 3H),        4.06 (m, 1H), 4.72 (m, 1H), 5.18 (s, 1H), 7.4 (m, 5H), 7.86 (d,        1H), 8.84 (s, 1H), 14.8 (s, 1H, D₂O exchangeable).

Example 10(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   4-Benzyloxycarbonylamino-3,3-dimethyl piperidine (100 g, 0.381        mol) was suspended in 200 ml acetonitrile under stirring. To the        solution was added        (1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylate        O³,O⁴) difluoroboron chelate (65 g, 0.189 mol) and stirring was        started at temperature between 25-35° C. The reaction mixture        was stirred for 4-5 hrs at this temperature. After the reaction        was completed, the solvent was removed under vacuum to dryness        to obtain a solid. To the solid was charged 200 ml ethyl alcohol        followed by triethylamine (20 g, 0.198 mol). The reaction        mixture was stirred at reflux temperature for 2-3 hrs. The        solution was left overnight at 25-35° C. The solid separated in        the reaction mixture was filtered and washed with 50 ml ethanol.        The filtered solid was stirred with reflux at 100-110° C. in        concentrated hydrochloric acid (250 ml) for 2 hr. The resulting        solution was taken to dryness by evaporating the acid under        vacuum to obtain a residue. To the residue was added 1 L acetone        and the suspension stirred for 1 hr. The resulting solid was        filtered and washed with acetone. The residue was suspended in        600 ml chloroform and was refluxed for 30 minutes. The        suspension was filtered and the residue washed with chloroform.        The residue was suspended in methanol (600 ml) and was stirred        at 30-35° C. for 30 minutes. The suspension was filtered to        obtain a solid, which was dissolved in 1 L water under stirring        at 60-70° C. The pH of the solution was adjusted between 8.0-9.0        by adding 30% aqueous sodium hydroxide solution. The reaction        mixture was extracted with 600 ml×2 chloroform. The organic        layers were combined and washed with water, dried over Na₂SO₄        and evaporated under reduced pressure to afford a solid which        was further triturated with methyl alcohol and filtered to give        43 g (56%) titled compound.    -   m/z (M+1) 404, mp 222-224° C.    -   NMR (CDCl₃): 0.95-1.3 (m, 10H); 1.7-1.8 (m, 2H); 2.6 (t, 1H);        3.0 (dd, 1H); 3.3 (m,2H); 3.6 (m, 1H), (3.7 s,3H); 4.02 (m, 1H),        7.9 (d,1H); 8.8 (s, 1H).    -   An alternate procedure to prepare this compound is by a method        similar to that described in Example 1 where        4-amino-3,3-dimethylpiperidine was used in place of        4-amino-3-methylpiperidine.    -   A second alternate procedure to prepare this compound is by        treating        1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-1-carbethoxyamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid [obtained from condensation of        1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylic        acid difluoroborane chelate and        4-1-carbethoxyamino-3,3-dimethylpiperidine] (2.0 g, 4.0 mmol)        under reflux with aqueous NaOH (0.6M, 100 ml) for 4 hr with        stirring, filtered and the residue dried. The obtained crude        product was adjusted to pH 3-5 by 3 N HCl, concentrated,        triturated with acetone and crystallisation from methanol        furnished the required product.

Example 11(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid.Hydrochloride

-   -   The hydrochloride salt was obtained by modifying the procedure        in Example 10 after obtaining the solid residue from filtration        of the suspension in methanol before dissolving in water and        adjusting the pH to 8.9 by adding 30% aqueous sodium hydroxide        solution. The residue obtained from filtration of the suspension        from methanol was dissolved in 2.0 ltr at reflux temperature. It        was then filtered hot and concentrated to approximately one        fourth of its volume and left overnight. The crystals obtained        were filtered at 25-35° C. and were dried in an oven at        70-80° C. under pump vacuum to yield 38.0 g (48%) titled        compound.    -   mp 256-260° C.,    -   NMR(CD₃OD): selected values 1.0-1.5 (m, 2H); 1.20 (d, 6H);        1.21-1.30 (m, 2H); 1.90-2.20 (m, 2H); 3.6-3.7 (m, 1H); 3.8        (s,3H); 4.20 (m, 1H), 7.8 (d,1H); 8.9 (s, 1H).

Example 12(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methanesulfonate

-   -   6.50 Grams (16.13 mol) of        1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid were suspended in 65 ml of isopropyl alcohol. The        suspension was heated to 70-80° C. under stirring and then 1.90        g (19.79 mol) methanesulfonic acid was added. The reaction        mixture was heated at reflux for 30 minutes. It was cooled to        30-35° C. and filtered. The solid was washed with 10 ml        isopropyl alcohol and dried for 16 hrs in oven under vacuum at        50° C. to give 6.80 g (84%) titled compound, mp 286-290° C.,    -   NMR (CD₃OD): selected values 1.0-1.5 (m, 2H); 1.20 (d, 6H);        1.9-2.2 (m, 2H); 2.7 (s, 3H); 3.2-3.7 (m, 4H); 3.8 (s,3H); 4.20        (m, 1H), 7.8 (d,1H); 8.9 (s, 1H).

Example 13(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid.gluconate

-   -   To a suspension of 2.50 g (6.20 mol)        1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid and 50 ml isopropyl alcohol was added 2.4 ml (1.50 g, 7.64        mol) 50% aqueous D-gluconic acid at 80° C. under stirring. The        clear solution was stirred for 30 minute at this temperature,        and cooled to 30-35° C. to give a solid. The solid was filtered        and washed with 10 ml isopropyl alcohol. The obtained solid was        crystallized from methanol to give 2.0 g (54%) of the gluconate        salt. mp. 160-162° C.

Example 14(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride

-   -   (+)-3,3-Dimethyl-4-^(t)-butyloxycarbonylamino piperidine (46 g,        0.201 mol) was suspended in 200 ml acetonitrile under stirring.        To the solution was added        (1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylate        O³,O⁴) difluoroboron chelate (35 g, 0.102 mol) and the reaction        mixture was stirred for 24 hrs between 25-35° C. temperature.        Triethylamine (10.3 g, 0.102 mol) was added to the reaction        mixture and it was stirred at 80-85° C. temperature for 4-5 hrs.        After reaction was completed, solvent was removed under vacuum        to dryness to obtain a residue. To the residue was charged 200        ml ethyl alcohol followed by triethylamine (12.32 g, 0.122 mol).        The reaction mixture was stirred at reflux temperature for 5-6        hrs. The solution was left overnight at 25-35° C. The solid        separated in the reaction mixture was filtered and washed with        50 ml ethanol. The solid was stirred with concentrated        hydrochloric acid (100 ml) for 1 hr. The resulting solution was        taken to dryness by evaporating the acid under vacuum to obtain        a residue. To the residue was added 600 ml acetone and the        suspension stirred for 1 hr. The resulting solid was filtered        and washed with acetone. The solid was suspended in 300 ml        chloroform and was refluxed for 30 minutes. The suspension was        filtered and was washed with chloroform. The wet solid was        suspended in methanol 100 ml and was stirred at 30-35° C. for 30        minutes. The reaction mixture was filtered. The residue was        dissolved in 1.3 L methanol at reflux temperature. It was        filtered hot and concentrated to approximately one fourth of        its, volume and was left overnight. Crystals obtained were        filtered at 25-35° C. and were dried in an oven at 70-80° C.        under vacuum to yield 15 g (33.5%) titled compound., mp 256-260°        C.,    -   NMR(CD₃OD): 0.95-1.3 (m, 10H); 1.90-2.20 (m, 2H); 3.15-3.4(m,        5H); 3.8 (s,3H); 4.20 (m, 1H), 7.8 (d,1H); 8.9 (s, 1H).    -   [α]_(D) ²⁵ value +132.0° (c=1, methanol).    -   The enantiomeric purity was established by making        N-^(t)-butyloxycarbonylalanine derivative of        (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid. This derivative was analyzed on HPLC against        N-^(t)-butyloxycarbonylalanine derivative of racemic        1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid.    -   The ratio of enantiomers was found to be 98.49:1.50.

Example 15(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride

-   -   The compound was prepared in 30% yield as per procedure        described for its (+) isomer.[α]_(D) ²⁵ value −127.27° (c=1,        methanol).    -   Enantiomeric purity was established by making        N-^(t)-butyloxycarbonylalanine derivative of        (−)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid. This derivative was analyzed on HPLC against        N-^(t)-butyloxycarbonylalanine derivative of racemic        1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid. The ratio of enantiomers was found to be 96.37:3.62.

Example 16(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   Grams (19.34 mmol) of        (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid hydrochloride were dissolved in 250 ml water under        stirring. The solution pH was adjusted between 8.0-9.0 by adding        30% aqueous sodium hydroxide solution. The reaction mixture was        extracted with 200 ml×2 chloroform. Combined organic layer was        washed with water, dried over Na₂SO₄ and evaporated under        reduced pressure to afford a solid which was further triturated        with isopropyl alcohol and filtered to give 7.34 g (94%) above        mentioned compound, mp 221-224° C.    -   NMR (CDCl₃): 0.95-1.3 (m, 10H); 1.7-1.8 (m, 2H); 2.6 (t, 1H);        3.0 (dd, 1H); 3.3 (m,2H); 3.6 (m, 1H), (3.7 s,3H); 4.02 (m, 1H),        7.9 (d,1H); 8.8 (s, 1H),    -   [αa]_(D) ²⁵ value +133.84° (c=1, chloroform).

Example 17(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   Similarly, by using the procedure mentioned above, 8.40 g (19.11        mmol) of        (−)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid hydrochloride was converted to 6.65 g (86%) titled        compound. mp 222-225° C., [α]_(D) ²⁵ value −125.060 (c=1,        chloroform).

Example 18 (+)1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid. Methanesulfonate

-   -   6.50 Grams (16.13 mmol) of        (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid were suspended in 65 ml of isopropyl alcohol. The        suspension was heated to 70-80° C. under stirring and then 1.90        g (19.79 mmol) methanesulfonic acid was added. The reaction        mixture became clear for a moment and a solid was separated. The        suspension was heated at reflux for 30 minutes. It was cooled to        30-35° C. and filtered. The solid was washed with 10 ml        isopropyl alcohol and dried for 16 hrs in oven under vacuum at        50° C. to give 6.80 g (84%) titled compound, mp 286-290° C.,    -   NMR (CD₃OD): 0.95-1.25 (m, 10H); 1.95-2.20 (m, 2H); 2.7 (s, 3H);        3.2-3.4 (m, 4H); 3.6-3.7 (m, 1H); 3.8 (s, 3H); 4.20 (m, 1H), 7.8        (d,1H); 8.9 (s, 1H).    -   [α]_(D) ²⁵ value +113.97° (c=1, methanol).

Example 19(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methanesulfonate

-   -   Similarly, by using the procedure mentioned above, 6.30 g (15.63        mmol) of        (−)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid was converted to 5.60 g (72%) titled compound, mp 288-290°        C.    -   [α]_(D) ^(b 25) value −112.41° (c=1, methanol).

Example 20(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate

-   -   To a suspension of 2.50 g (6.20 mmol)        (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid and 50 ml isopropyl alcohol was added 2.4 ml (1.50 g, 7.64        mmol) 50% aqueous D-gluconic acid at 80° C. under stirring. The        clear solution was stirred for 30 minute at this temperature,        cooled to 30-35° C. to give a solid. The solid was filtered and        washed with 10 ml isopropyl alcohol. The obtained solid was        crystallized from methanol to give 2.0 g (54%) gluconate salt of        (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid, mp 158-60° C.

Example 21(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate

-   -   Similarly, by using the procedure mentioned above, 2.20 g (54.60        mmol) of        (−)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic        acid was converted to 1.65 g (50%) titled compound, mp 154-156°        C.

Example 221-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-acetylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-acylamino-3,3-dimethylpiperidine was used in place of        4-amino-3-methylpiperidine. Yield 20%, m.p.194-96° C.,        C₂₃H₂₈FN₃O₅, m/z 446 (M+1).

Example 231-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-^(t)-butyloxycarbonylamino-3,3-dimethyl-1-piperidinyl)}-4-oxo-quinoline-3-carboxylicacid

-   -   Di-t-butoxycarbonate (0.32 g, 1.1 mmol) was added to a stirred        solution of        1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)}-4-oxo-quinoline-3-carboxylic        acid (0.3 g, 7.4 mmol) in dioxane (10 ml) and water (5 ml) at        ambient temperature and stirring was continued for 14 hr and        concentrated to dryness. The obtained solid was dissolved in        ethyl acetate, washed with water, dried (Na₂SO₄) and        concentrated to give titled product. Yield 72%, m.p.218-20° C.,        C₂₆H₃₄FN₃O₆, m/z 504 (M+1).

Example 241-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,3-dimethyl-1-piperidinyl)}-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-methylamino-3,3-dimethylpiperidine was used in place of        4-amino-3-methylpiperidine Yield 50%, m.p.246-48° C.,        C₂₂H₂₈FN₃O₄, m/z 418 (M+1).

Example 251-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,3-dimethyl-1-piperidinyl)}-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-ethylamino-3,3-dimethylpiperidine was used in place of        4-amino-3-methylpiperidine Yield 60%, m.p.230-32° C.,        C₂₃H₃₀FN₃O₄, m/z 432 (M+1).

Example 261-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,3-dimethyl-1-piperidinyl)}-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-cyclopropyl amino-3,3-dimethylpiperidine was used in        place of 4-amino-3-methylpiperidine Yield 31%, m.p.190-92° C.,        C₂₄H₃₀FN₃O₄, m/z 444 (M+1), PMR (CDCl₃): 1.22 (6H, s), 0.8-1.48        (8H, m), 1.88 (2H, m), 2.28-3.7 (6H, m), 3.72 (s, 3H), 4.06 (m,        1H), 7.74 (d, 1H), 8.74 (s, 1H), 14.7 (bs, 1H, D₂O        exchangeable).

Example 271-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-dimethyl amino-3,3-dimethylpiperidine was used in place        of 4-amino-3-methylpiperidine Yield 35%, m.p.210° C.,        C₂₃H₃₀FN₃O₄, m/z 432 (M+1), PMR (CDCl₃): 1.02 (d, 6H), 0.92-1.4        (m, 4H), 1.8 (m, 2H), 2.32 (s, 6H) 2.28-3.65 (m, 5H), 3.58 (s,        3H), 4.01 (m, 1H, m), 7.68 (d, 1H), 8.86 (s, 1H), 14.9 (bs, 1H,        D₂O exchangeable).

Example 281-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-{4-amino-3-ethyl-3-methyl-1-piperidinyl}-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-amino-3-ethyl-3-methylpiperidine was used in place of        4-amino-3-methylpiperidine. m.p. 152-54° C., C₂₂H₂₈FN₃O₄, m/z        418 (M+1).

Example 291-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-ethyl-3-methyl-1-piperidinyl)}-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-methylamino-3-ethyl-3-methylpiperidine was used in place        of 4-amino-3-methylpiperidine m.p. 182-84° C., C₂₃H₃₀FN₃O₄, m/z        432 (M+1).

Example 301-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-ethyl-3-methyl-1-piperidinyl)}-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-cyclopropyl amino-3-ethyl-3-methylpiperidine was used in        place of 4-amino-3-methylpiperidine m.p. 210-12° C.,        C₂₅H₃₂FN₃O₄, m/z 458 (M+1).

Example 311-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-dimethyl amino-3-ethyl-3-methylpiperidine was used in        place of 4-amino-3-methylpiperidine, m.p.210-12° C.,        C₂₄H₃₂FN₃O₄, m/z 446 (M+1).

Example 32 Mixtures A+B of1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-amino-3,5-dimethylpiperidine was used in place of        4-amino-3-methylpiperidine, m.p.178-80° C., C₂₁H₂₆FN₃O₄, m/z 404        (M+1).

Example 33 Mixture A of isomers of1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where Mixture A of isomers of 4-amino-3,5-dimethylpiperidine was        used in place of 4-amino-3-methylpiperidine, m.p. 238-40° C.,        C₂₁H₂₆FN₃O₄, m/z 404 (M+1).

Example 34 Mixture B of isomers of1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where Mixture B of isomers of 4-amino-3,5-dimethylpiperidine was        used in place of 4-amino-3-methylpiperidine, m.p. 200-04° C.,        C₂₁H₂₆FN₃O₄, m/z 404 (M+1).

Example 35 Mixtures A+B of1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-{4-methylamino-3,5-dimethyl-1-piperidinyl)}-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-methylamino-3,5-dimethylpiperidine was used in place of        4-amino-3-methylpiperidine, m.p. 268-72° C., C₂₂H₂₈FN₃O₄, m/z        418 (M+1).

Example 36 Mixture A of isomers of1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where Mixture A of isomers of        4-methylamino-3,5-dimethylpiperidine was used in place of        4-amino-3-methylpiperidine, C₂₂H₂₈FN₃O₄, m/z418 (M+1).

Example 37 Mixture B of isomers of1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where Mixture A of isomers of        4-methylamino-3,5-dimethylpiperidine was used in place of        4-amino-3-methylpiperidine, C₂₂H₂₈FN₃O₄, m/z 418 (M+1).

Example 38 Mixture A of isomers of1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where Mixture A of isomers of        4-methylamino-3,5-dimethylpiperidine was used in place of        4-amino-3-methylpiperidine, m.p. 250-52° C., C₂₃H₃₀FN₃O₄, m/z        432 (M+1).

Example 39 Mixture B of isomers of1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where Mixture B of isomers of        4-methylamino-3,5-dimethylpiperidine was used in place of        4-amino-3-methylpiperidine, m.p. 250-55° C., C₂₃H₃₀FN₃O₄, m/z        432 (M+1).

Example 40 Mixture A of isomers of1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where Mixture A of isomers of 4-cyclopropyl        amino-3,5-dimethylpiperidine was used in place of        4-amino-3-methyl-piperidine, C₂₄H₃₀FN₃O₄, m/z 444 (M+1)

Example 41 Mixture B of isomers of1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where Mixture B of isomers of 4-cyclopropyl        amino-3,5-dimethylpiperidine was used in place of        4-amino-3-methyl-piperidine, m.p. 240-42° C., C₂₄H₃₀FN₃O₄, m/z        444 (M+1)

Example 421-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3,5-trimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 1,        where 4-amino-3,3,5-trimethylpiperidine was used in place of        4-amino-3-methylpiperidine, m.p. 218-20° C., C₂₂H₂₈FN₃O₄, m/z        418 (M+1).

Example 435-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   A suspension of        5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylic        acid (0.17 g, 0.55 mmol), 3,3-dimethyl-4-methylamino piperidine        (0.15 g, 1.06 mmol) and triethylamine (1 g, 10 mmol) in a        mixture of dimethylsulfoxide (10 ml) and acetonitrile (10 ml)        was heated at 70° C. for 18 hr. Acetonitrile was distilled off,        filtered to remove suspended impurities, diluted with water (5        ml). The precipitate thus separated was filtered, washed with        water, dried and purified by silicagel column chromatography.        Elute from a mixture of ethyl acetate and methanol furnished the        required product. Yield 0.12 g (50%), m.p.250° C. (decomp.),        C₂₂H₂₉FN₄O₄, m/z 433 (M+1), PMR (DMSO-d₆): 0.9 (m, 2H), 1.0 (m,        2H), 1.0 (s, 3H), 1.1 (s, 3H), 1.8-2.0 (m, 2H), 2.6 (s, 3H),        2.8-3.2 (m, 4H), 3.5 (s, 3H), 3.6 (s, 3H), 3.65 (m, 1H), 4.0 (m,        1H), 7.2 (bs, 2H, D₂O exchangeable), 8.6 (s, 1H).

Example 445-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-amino-3-methylpiperidine was used in place of        3,3-dimethyl-4-methylaminopiperidine. Yield 40%, m.p. 260-62°        C., C₂₀H₂₅FN₄O₄, m/z 405 (M+1), PMR (CD₃OD): 0.8-1.18 (m, 7H),        1.8-2.2 (m, 3H), 2.82-3.54 (m, 5H), 3.6 (s, 3H), 4.01 (m, 1H),        8.62 (s, 1H).

Example 455-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-methyl-1-piperidinyl)-4-oxo-quinolin-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-methylamino-3-methylpiperidine was used in place of        3,3-dimethyl-4-methylamino piperidine. Yield 30%, m.p.228-30° C.        (decomp.), C₂₁H₂₇FN₄O₄, m/z 419 (M+1).

Example 465-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-ethyl amino-3-methylpiperidine was used in place of        3,3-dimethyl-4-methylamino piperidine. Yield 35%, m.p.230-32°        C., C₂₂H₂₉FN₄O₄, m/z 433 (M+1).

Example 475-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-cyclo propylamino-3-methylpiperidine was used in place        of 3,3-dimethyl-4-methyl aminopiperidine. Yield 35%, m.p.218-20°        C., C₂₃H₂₉FN₄O₄, m/z 445 (M+1).

Example 485-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-dimethylamino-3-methylpiperidine was used in place of        3,3-dimethyl-4-methylamino piperidine. Yield 30%, m.p.210° C.,        C₂₂H₂₉FN₄O₄, m/z 433 (M+1), PMR (CD₃OD): 0.81-1.22 (m, 7H),        1.8-2.25 (m, 3H), 2.92 (s, 6H), 2.61-3.52 (m, 5H), 3.61 (s, 3H),        4.04 (m, 1H), 8.62 (s, 1H).

Example 495-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 44,        where 4-amino-3,3-dimethylpiperidine was used in place of        3,3-dimethyl-4-methylaminopiperidine, m.p.205° C., C₂₁H₂₇FN₄O₄,        mm/z 419 (M+1), PMR (DMSO-d₆): 0.8 (m, 2H), 1.0 (m, 2H), 1.0 (s,        3H), 11 (s, 3H), 1.4-1.6 (m, 2H), 2.6-2.8 (m, 4H), 3.6 (s, 3H),        3.65 (m, 1H), 4.0 (m, 1H), 6.2 (bs, 2H, D₂O exchangeable), 7.2        (bs, 2H, D₂O exchangeable), 8.6 (s, 1H).

Example 505-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,3-dimethyl-1-piperidinyl)}-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-ethylamino-3,3-dimethylpiperidine was used in place of        3,3-dimethyl-4-methylaminopiperidine, m.p.205° C. (decomp.),        C₂₃H₃₁FN₄O₄, m/z 447 (M+1), PMR (CDCl₃): 0.8 (m, 2H), 1.0 (m,        2H), 1.05 (s, 3H), 1.1 (s, 3H), 1.2 (t, 3H), 1.6-2.0 (m, 2H),        2.4-2.8 (m, 6H), 3.5 (s, 3H), 3.6 (m, 1H), 3.9 (m, 1H), 6.4 (bs,        2H, D₂O exchangeable), 8.4 (bs, 1H, D₂O exchangeable), 8.8 (s,        1H).

Example 515-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-dimethylamino-3,3-dimethylpiperidine was used in place        of 3,3-dimethyl-4-methyl-aminopiperidine, m.p.178° C. (decomp.),        C₂₃H₃₁FN₄O₄, m/z 447 (M+1).

Example 52 Mixture A of Isomers of5-amino-1-cyclopropyl)-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where Mixture A of isomers of 4-amino-3,5-dimethylpiperidine was        used in place of 3,3-dimethyl-4-methylamino piperidine,        m.p.238-40° C., C₂₁H₂₇FN₄O₄, m/z 419 (M+1),

Example 53 Mixture B of Isomers of5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where Mixture B of isomers of 4-amino-3,5-dimethylpiperidine was        used in place of 3,3-dimethyl-4-methylamino-piperidine, m.p.        248-50° C. (decomp.), C₂₁H₂₇FN₄O₄, m/z 419 (M+1).

Example 545-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-methylamino-3,5-dimethylpiperidine was used in place of        3,3-dimethyl-4-methylaminopiperidine, m.p. 224-26° C.,        C₂₂H₂₉FN₄O₄, m/z 433 (M+1).

Example 55 Mixture A of Isomers of5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid,

-   -   It was prepared in a similar manner as described in Example 43,        where Mixture A of isomers of        4-methylamino-3,5-dimethylpiperidine was used in place of        3,3-dimethyl-4-methylaminopiperidine, C₂₂H₂₉FN₄O₄, m/z 433        (M+1).

Example 56 Mixture B of Isomers of5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where Mixture B of isomers of        4-methylamino-3,5-dimethylpiperidine was used in place of        3,3-dimethyl-4-methyl-aminopiperidine, C₂₂H₂₉FN₄O₄, m/z 433        (M+1).

Example 57 Mixture A of Isomers of5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where Mixture A of isomers of        4-ethylamino-3,5-dimethylpiperidine was used in place of        3,3-dimethyl-4-methyl-aminopiperidine. Yield 52% m.p. 202-4° C.,        C₂₃H₃₁FN₄O₄, m/z 447 (M+1).

Example 58 Mixture B of Isomers of5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where Mixture B of isomers of        4-ethylamino-3,5-dimethylpiperidine was used in place of        3,3-dimethyl-4-methyl-aminopiperidine. Yield 80%, m.p. 255-58°        C., C₂₃H₃₁FN₄O₄, m/z 447 (M+1).

Example 59 Mixture A of isomers of5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where Mixture A of isomers of        4-cyclopropylamino-3,5-dimethylpiperidine was used in place of        3,3-dimethyl-4-methylaminopiperidine, C₂₄H₃₁FN₄O₄, m/z 459 (M+1)

Example 60 Mixture B of Isomers of5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where Mixture B of isomers of        4-cyclopropylamino-3,5-dimethylpiperidine was used in place of        3,3-dimethyl-4-methylaminopiperidine, m.p. 248° C., C₂₄H₃₁FN₄O₄,        m/z 459 (M+1)

Example 615-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-amino-3-ethyl-3-methylpiperidine was used in place of        3,3-dimethyl-4-methylaminopiperidine, m.p. 210° C. (decompose),        C₂₂H₂₉FN₄O₄, m/z 433 (M+1).

Example 625-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-ethyl-3-methyl-1-piperidinyl)}-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-methylamino-3-ethyl-3-methylpiperidine was used in place        of 3,3-dimethyl-4-methylaminopiperidine, m.p. 164-66° C.,        C₂₃H₃₁FN₄O₄, m/z 447 (M+1).

Example 635-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-ethyl-3-methyl-1-piperidinyl)}-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-cyclopropyl amino-3-ethyl-3-methylpiperidine was used in        place of 3,3-dimethyl-4-methylaminopiperidine, m.p. 186-88° C.,        C₂₅H₃₃FN₄O₄, m/z 473 (M+1).

Example 645-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-dimethyl amino-3-ethyl-3-methylpiperidine was used in        place of 3,3-dimethyl-4-methylaminopiperidine, m.p. 194-96° C.,        C₂₄H₃₃FN₄O₄, m/z 461 (M+1).

Example 655-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3,5-Trimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   It was prepared in a similar manner as described in Example 43,        where 4-amino-3,3,5-trimethylpiperidine was used in place of        3,3-dimethyl-4-methylaminopiperidine, m.p. 248-52° C.,        C₂₂H₂₉FN₄O₄, m/z 433 (M+1).

Example 66trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   A mixture of        [1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0³,0⁴]difluoroboron        (0.5 g,1.52 mmol), and trans-4-amino-3-methylpiperidine (0.86 g,        7.64 mmol) in 10 ml acetonitrile was heated to reflux for 8 hr.        The reaction mixture was concentrated to dryness. The obtained        residue was treated with 10 ml ethanol and triethylamine (0.154        ml,1.52 mmol) and refluxed for 3 hr. Solvent was evaporated to        dryness under reduced pressure and the residue was purified on        preparative HPLC to give titled product, m. p. 223-225° C.        C₂₀H₂₄FN₃O₃, m/z 374 (M+1), PMR (CD3OD): 0.85 (m, 2H), 1.05 (d,        3H), 1.2 (m, 2H), 1.7-2.1(m, 3H), 2.8 (s, 3H), 2.9-3.1(m, 3H),        3,3-3.4(m,2H), 4.25 (m, 1H),7.8(d,1H), 8.9(s,1H).

Example 67cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        66, by using cis-4-amino-3-methylpiperidine, m. p. 224-228° C.,        C₂₀H₂₄FN₃O₃, m/z 374 (M+1), PMR (CD3OD): 0.8-1.0 (m, 2H), 1.15        (d,3H), 1.15-1.25(m, 2H),1.8-2.3(m, 3H), 2.8 (s, 3H),3.1-3.4(m,        3H), 3.4-3.6(m,2H), 4.25 (m, 1H),7.8(d,1H), 8.9(s,1H).

Example 68(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        66, by using (±)-4-amino-3,3-dimethylpiperidine, m. p.        198-200° C. C₂₁H₂₆FN₃O₃, m/z 388 (M+1), PMR (CD3OD): 0.8-1.1 (m,        2H), 1.10 (d, 6H), 1.1-1.4 (m, 2H),1.9-2.2 (m, 2H), 2.8 (s, 3H),        2.9-3.1(m, 1H), 3.2-3.4 (m,3H), 4.3 (m, 1H),7.8 (d,1H), 8.9        (s,1H).

Example 69(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        66, by using (−)-4-amino-3,3-dimethylpiperidine, m. p. 195-198°        C., C₂₁H₂₆FN₃O₃, m/z 388 (M+1).

Example 70(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-744-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        66, by using (+)-4-amino-3,3-dimethylpiperidine, m. p. 195-198°        C., C₂₁H₂₆FN₃O₃, m/z 388 (M+1).

Example 711-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-methylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        66, by using 4-methylamino-3-methylpiperidine, m. p 233-235° C.,        C₂₁H₂₆FN₃O₃, m/z 388 (M+1), PMR (CD3OD): 0.8-1.4 (m, 7H),        1.9-2.4 (m, 3H), 2.8 (s, 3H), 2.9 (s, 3H), 3.2-3.7 (m, 5H), 4.3        (m, 1H),7.9 (d,1H), 8.9 (s,1H).

Example 721-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-dimethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        66, by using 4-dimethylamino-3-methylpiperidine, m. p. 221° C.,        C₂₂H₂₈FN₃O₃, m/z 402 (M+1), PMR (CD3OD): 0.8-1.4 (m, 7H),        2.0-2.2 (m, 2H),2.5 (m, 2H), 2.8 (s, 3H), 3.0 (s, 6H), 3.2-3.7        (m,4H), 4.4 (m, 1H),7.8 (d,1H), 8.95 (s,1H).

Example 731-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-ethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        66, by using 4-ethylamino-3,3-dimethylpiperidine, m. p. 201-203°        C., C₂₃H₃₀FN₃O₃, m/z 416 (M+1), PMR (CD3OD): 0.8-1.1 (m, 2H),        1.2-1.5 (m, 11H),2.0-2.2 (m, 2H), 2.8 (s, 3H), 2.9-3.5 (m, 7H),        4.3 (m, 1H),7.9 (d,1H), 9.0 (s,1H).

Example 741-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-dimethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        66, by using 4-dimethylamino-3,3-dimethylpiperidine, m. p.        209-210° C., C₂₃H₂₉FN₃O₃, m/z 416 (M+1), PMR (CD3OD): 0.8-1.0        (m, 2H), 1.05-1.40 (m, 8H),2.0-2.2 (m, 2H), 2.5-3.1 (m, 10H),        3.2-3.6 (m, 3H), 4.3 (m,1H), 7.9 (d,1H), 9.0 (s,1H).

Example 75trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   A mixture of        [1-cyclopropyl-6,7-difluoro-8-ethyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0³,0⁴]difluoroboron        (0.5 g,1.49 mmol), and trans-4-amino-3-methylpiperidine (0.86 g,        7.64 mmol) in 10 ml acetonitrile was heated to reflux for 8 hr.        The reaction mixture was concentrated to dryness. The obtained        residue was treated with 10 ml ethanol and triethylamine (0.154        ml, 1.52 mmol) and refluxed for 3 hr. Solvent was evaporated to        dryness under reduced pressure and the residue was purified on        preparative HPLC to give titled product, C₂₁H₂₆FN₃O₃, m/z 388        (M+1), PMR (CD3OD): 0.9-1.3 (m, 10H), 1.8-2.2 (m, 2H), 2.9-3.7        (m, 8H), 4.2 (m, 1H), 7.9 (d,1H), 9.0 (s,1H).

Example 76cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        75, by using cis-4-amino-3-methylpiperidine, C₂₁H₂₆FN₃O₃, m/z        388 (M+1), PMR (CD3OD): 0.8-1.4 (m, 10H), 1.8-2.4 (m, 3H),        3.0-3.8 (m, 9H), 4.2 (m, 1H), 1.79 (d,1H), 9.0 (s,1H).

Example 77(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        75, by using (±)-4-amino-3,3-dimethylpiperidine, C₂₂H₂₈FN₃O₃,        m/z 402 (M+1), PMR (CD3OD): 0.8-1.3 (m, 13H), 1.6-2.0 (m, 2H),        2.7-3.0 (m, 2H), 3.0-3.8 (m, 5H), 4.1 (m, 1H), 7.8 (d,1H), 8.9        (s,1H).

Example 78(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        75, by using (−)-4-amino-3,3-dimethylpiperidine, C₂₂H₂₈FN₃O₃,        m/z 402 (M+1).

Example 79(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        75, by using (+)-4-amino-3,3-dimethylpiperidine, C₂₂H₂₈FN₃O₃,        m/z 402 (M+1).

Example 801-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        75, by using 4-aminopiperidine, m.p. 248-249° C. C₂₀H₂₄FN₃O₃,        m/z 374 (M+1), PMR (CD3OD): selected values 0.9 (m, 2H), 1.1 (t,        3H), 1.3 (m, 2H), 1.7-2.2 (m, 4H), 3.6 (m, 2H), 4.2 (m,1H),        7.9(d,1H), 9.0 (s, 1H).

Example 81trans-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   A mixture of        [1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0³,0⁴]difluoroboron        (0.5 g, 1.46 mmol), and trans-4-amino-3-methylpiperidine (0.86        g, 7.64 mmol) in 10 ml acetonitrile was heated to reflux for 8        hr. The reaction mixture was concentrated to dryness. The        obtained residue was treated with 10 ml ethanol and        triethylamine (0.154 ml,1.52 mmol) and refluxed for 3 hr.        Solvent was evaporated to dryness under reduced pressure and the        residue was purified on preparative HPLC to give titled product,        C₂₀H₂₅FN₄O₃, m/z 389 (M+1),

Example 82cis-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        81, by using cis-4-amino-3-methylpiperidine, C₂₀H₂₅FN₄O₃, m/z        389 (M+1).

Example 83(±)-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        81, by using (±)-4-amino-3,3-dimethylpiperidine, C₂₁H₂₇FN₄O₃,        m/z 403 (M+1).

Example 84(−)-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        81, by using (−)-4-amino-3,3-dimethylpiperidine, C₂₁H₂₇FN₇O₃,        m/z 403 (M+1).

Example 85(+)-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure as described in Example        81, by using -(+)-4-amino-3,3-dimethylpiperidine, C₂₁H₂₇FN₇O₃,        m/z 403 (M+1).

Example 86cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride

-   -   A mixture of        [1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0³,0⁴]difluoroboron        (2.4 g, 7.34 mmol), and        cis-4-t-butyloxycarbonylamino-3-methylpiperidine (4.45 g, 20.8        mmol) in 10 ml acetonitrile was stirred at 50° C. for 30 hr. The        reaction mixture was concentrated to dryness. The obtained        residue was treated with 10 ml ethanol and 1 ml triethylamine        and refluxed for 1 hr. Solvent was evaporated to dryness under        vacuum and the residue was purified by silica gel column        chromatography using 3% methanol chloroform solvent mixture as        an eluent to give a crude product. The crude product was        dissolved in 10 ml conc HCl and stirred for 30 minutes. The        solvent was evaporated under vacuum. The resultant solid was        dissolved in methanol and re-crystallized by adding ethyl        acetate to provide titled compound 1.56 g (52%) yield as a        solid. m. p. 255-260° C. C₂₀H₂₅FN₃O₃Cl, m/z 374 (M+1), PMR        (CD₃OD): 0.95 (m, 2H), 1.2 (d, 3H), 1.2-1.4 (m, 2H), 1.8-2.4 (m,        3H), 2.8 (s, 3H), 3.2-3.4 (m, 3H), 3.5-3.7 (m, 2H), 4.3 (m,        1H),7.8 (d,1H), 9.0 (s,1H).

Example 87trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride

-   -   The compound was prepared by a procedure described in Example 86        by using trans-4-t-butyloxycarbonylamino-3-methylpiperidine        instead cis-4-t-butyloxycarbonylamino-3-methylpiperidine.    -   Yield: 56% m. p. 262-265° C. C₂₀H₂₅FN₃O₃Cl, m/z 374 (M+1).

Example 88cis/trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure described in Example 86        by using cis/trans-4-hydroxy-3-methylpiperidine instead of        trans4-amino-3-methylpieridine and product was purified on        preparative HPLC to give titled product. M. p. 202-206° C., mass        (ES⁺) 375, Molecular Formula C₂₀H₂₃FN₂O₄, H¹NMR (CD3OD) 0.92 (s,        2H), 1.04 (d, 3H), 1.22-1.38 (m, 2H), 1.62-1.82 (m, 2H),        1.82-2.1 (m, 2H), 2.8 (s, 3H), 2.90-3.24 (m, 4H), 3.95 (q, 1H),        4.30 (m, 1H), 7.80-7.88 (d, 1H), 8.95 (s, 1H).

Example 89 cis-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure described in Example 86        by using cis-4-hydroxy-3-methylpiperidine instead of        trans-4-amino-3-methylpieridine and product was purified on        preparative HPLC to give titled product. M. p. 206-210° C., mass        (ES³⁰ ) 375, Molecular Formula C₂₀H₂₃FN₂O₄, H¹NMR (CD₃OD) 0.92        (s, 2H), 1.04 (d, 3H), 1.22-1.38 (m, 2H), 1.62-1.82 (m, 2H),        1.82-2.10 (m, 2H), 2.8 (s, 3H), 3.0-3.15 (s, 1H), 3.22-3.40 (s,        1H), 3.50-3.62 (m, 2H), 4.0-4.10 (q, 1H), 4.10-4.20 (m, 1H),        7.80-7.88 (d, 1H), 8.95 (s, 1H).

Example 90trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure described in Example 86        by using trans-4-hydroxy-3-methylpiperidine instead of        trans-4-amino-3-methylpieridine and product was purified on        preparative HPLC to give titled product. M. p. 214-216° C., mass        (ES³⁰ ) 375, Molecular Formula C₂₀H₇₃FN₂O₄, H¹NMR (CD₃OD) 0.92        (s, 2H), 1.04 (d, 3H), 1.22-1.38 (m, 2H), 1.62-1.82 (m, 2H),        1.82-2.10 (m, 2H), 2.8 (s, 3H), 3.0-3.15 (s, 1H), 3.22-3.40 (s,        1H), 3.50-3.62 (m, 2H), 4.04.10 (q, 1H), 4.10-4.20 (m, 1H),        7.80-7.88 (d, 1H), 8.95 (s, 1H).

Example 91cis/trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure described in Example 86        by using cis/trans-4-hydroxy-3-ethylpiperidine instead of        trans-4-amino-3-methylpieridine and product was purified on        preparative HPLC to give titled product. m. p. 185-190° C., mass        (ES³⁰ ) 389, Molecular Formula C₂₁H₂₅FN₂O₄, H¹NMR (CD₃OD)        0.92-1.02 (m, 7H), 1.22-2.18 (m, 4H), 2.78 (s, 3H), 2.90-3.72        (m, 4H), 4.15 (q, 1H), 7.85-7.98 (d, 1H), 8.95 (s, 1H).

Example 92cis/trans-1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure described in Example 86        by using cis/trans-4-hydroxy-3-ethylpiperidine instead of        trans-4-amino-3-methylpieridine and product was purified on        preparative HPLC to give titled product. m. p. 170-172° C., mass        (ES³⁰ ) 403, Molecular Formula C₂₂H₂₇FN₂O₄, H¹NMR (CD₃OD)        0.92-1.02 (m, 10H), 1.22-2.18 (m, 6H), 2.80-3.62 (m, 4H),        4.0-4.22 (m, 2H), 7.86-8.02 (d, 1H), 8.95 (s, 1H).

Example 93cis/trans-1-Cyclopropyl-6-fluoro-8-methoxy-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure described in Example 1        by using cis/trans-4-hydroxy-3-methylpiperidine instead of        4-amino-3-methylpiperidine and product was purified on        preparative HPLC to give titled product. m. p. 114-216° C., mass        (ES³⁰ ) 391, Molecular Formula C₂₀H₂₃FN₂O₅, H¹NMR (CDCl₃)        1.00-1.12 (m, 4H), 1.20-1.32 (d, 3H), 1.78-2.22 (m, 3H),        2.20-2.70 (m, 4H), 3.58-3.80 (s,3H), 4.00-4.18 (m, 1H), 7.82-8.0        (d, 1H), 8.82 (s, 1H).

Example 94cis/trans-1-Cyclopropyl-6-fluoro-8-methoxy-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

-   -   The compound was prepared by a procedure described in Example 1        by using cis/trans-4-hydroxy-3-ethylpiperidine instead of        4-amino-3-methylpiperidine and product was purified on        preparative HPLC to give titled product. m. p. 188-190° C., mass        (ES³⁰ ) 405, Molecular Formula C₂₁H₂₅FN₂O₅, H¹NMR (CHCl₃)        0.98-1.05 (t, 3H), 1.06-1.58 (m, 4H), 1.60-2.02 (m, 3H), 3.30        (s, 3H), 3.60-3.75 (m, 4H), 3.75-3.90 (q, 3H), 4.00-4.20 (m,        2H), 7.85-7.98 (d, 1H), 8.80 (s, 1H).

Example 95cis/trans-5-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

-   -   The above compound was prepared by a procedure described in        Example 43 by using cis/trans-4-hydroxy-3-methylpiperidine        instead of 3,3-dimethyl-4-methylaminopiperidine and product was        purified on preparative HPLC to give titled product.    -   m. p. 240-244° C., mass (ES³⁰ ) 406, Molecular Formula        C₂₀H₂₄FN₃O₅.

Example 96cis/trans-5-Amino-1-cyclopropyl-6-fluoro-8-methoxy-3-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

The above compound was prepared by a procedure described in Example 43by using cis/trans-4-hydroxy-3-ethylpiperidine instead of3,3-dimethyl-4-methylaminopiperidine and product was purified onpreparative HPLC to give titled product.

m. p. 217-19° C., mass (ES³⁰ ) 420, Molecular Formula C₂₁H₂₆FN₃O₅,

H¹NMR (CDCl₃) 0.82 (d, 2H), 1.02 (t, 3H),1.18 (d, 2H), 3.18-3.40 (m,4H), 3.60 (s, 3H), 3.90-4.02 (q, 2H), 4.18 (m, 1H), 8.70 (s, 1H).

Example 97(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride

The product obtained in example 68 (1 gm; 2.58 mmol) was suspended in 10ml ethanol and ethanolic hydrochloric acid (2.6 ml) was added at atemperature between 20-30° C. under stirring. To this solution, 20 mlether was added after 30 minutes and the solid separated was filteredand dried under vacuum. Yield—0.89 gm (83%). m. p. 242-244° C.,C₂₁H₂₆FN₃O₃.HCl, m/z 388 (M+1).

Similarly by using above procedure other inorganic acid salts are made.

Example 98(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride

The product obtained in example 69 (1 gm; 2.58 mmol) was suspended in 10ml ethanol and ethanolic hydrochloric acid (2.6 ml) was added at atemperature between 20-30° C. under stirring. To this solution, 20 mlether was added after 30 minutes and the solid separated was filteredand dried under vacuum. Yield—0.91 gm (83%). m. p.(by DSC) 300°°C.C₂₁H₂₆FN₃O₃.HCl, m/z 388 (M+1), [α]_(D) ²⁵ value=−278.14° (c=0.5,methanol).

Similarly by using above procedure other inorganic acid salts are made.

Example 99(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl-4-oxo-quinoline-3-carboxylicacid hydrochloride

The product obtained in example 70 (1 gm; 2.58 mmol) was suspended in 10ml ethanol and ethanolic hydrochloric acid (2.6 ml) was added at atemperature between 20-30° C. under stirring. To this solution, 20 mlether was added after 30 minutes and the solid separated was filteredand dried under vacuum. Yield—0.86 gm (83%). m. p. (by DSC) 300° C.,C₂₁H₂₆FN₃O₃.HCl, m/z 388 (M+1), [α]D²⁵ value=−275° (c=0.5, methanol).

Similarly by using above procedure other inorganic acid salts are made.

Example 100(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate

The product obtained in example 68 (1 gm; 2.58 mmol) was suspended in 10ml isopropyl alcohol. The reaction mixture was heated to 70 to 80° C.Methane sulfonic acid (0.25 g, 2.6 mmol) was added. The reaction mixturewas cooled after 30 minutes f refluxing and was filtered at 10 to 20°C., dried under vacuum. Yield—0.76 gm (60%). C₂₁H₂₆FN₃O₃.CH₄SO₃, m/z 388(M+1).

Similarly by using above procedure other organic acid salts are made.

Example 101(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate

The product obtained in example 69 (1 gm; 2.58 mmol) was suspended in 10ml isopropyl alcohol. The reaction mixture was heated to 70 to 80° C.Methane sulfonic acid (0.25 g, 2.6 mmol) was added. The reaction mixturewas cooled after 30 minutes f refluxing and was filtered at 10 to 20°C., dried under vacuum. Yield—0.80 gm (64%). C₂₁H₂₆FN₃O₃.CH₄SO₃, m/z 388(M+1).

Similarly by using above procedure other organic acid salts are made.

Example 102(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate

The product obtained in example 70 (1 gm; 2.58 mmol) was suspended in 10ml isopropyl alcohol. The reaction mixture was heated to 70 to 80° C.Methan sulfonic acid (0.25 g, 2.6 mmol) was added. The reaction mixturewas cooled after 30 minutes f refluxing and was filtered at 10 to 20°C., dried under vacuum. Yield—0.83 gm (66%). C₂₁H₂₆FN₃O₃.CH₄SO₃, m/z 388(M+1).

Similarly by using above procedure other organic acid salts are made.

TEST EXAMPLE-1 X-ray Diffraction Analysis

300 mg of racemic or optically active1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride was thinly spread on a sample holder. X-raydiffraction analyses (40 kv×40 mA Rigaku D/max 2200) were performedunder the conditions listed below:

-   -   Scan speed 5°/min    -   Sampling time 7 min    -   Scan mode: continuous    -   2θ/θ reflection    -   Cu target (Ni filter)

TEST EXAMPLE 2 Differential Scanning Calorimetry Analysis ThermalAnalysis of Racemic or Optically Active1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride

For the Differential Scanning Calorimetry, PERKINELMER DSC-7 system wasused. 3 to 5 mg of the sample was weighed into the aluminum pan, whichwas then press sealed with an aluminum lid. The sample was tested byheating from 30° C. to 350° C. at a rate of 10° C./min.

TEST EXAMPLE-3 Infra-Red Spectrum Infra-Red Spectrum Analysis of Racemicor Optically Active1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride

A KBr pellet of the sample (2% w/w) was scanned on Bruker FT-IRspectrophotometer. The instrument was calibrated with polystyrene film.Scan range 4000 cm⁻¹ to 400 cm⁻¹. Resolution 2 cm⁻¹. Scan time 16 scans.

Example 103 Crystalline polymorphic form of(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride—Polymorph A1

50 gm of(±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride was dissolved in 4.0 liter methanol at refluxtemperature. The clear solution was filtered through a celite bed andthe resultant solution was concentrated to approximately 1 liter, cooledto a temperature between 25-35° C. and filtered under suction after 12hours. The solid obtained was further dried at 70° C. under vacuum toprovide crystalline material (35.6 gm).

The polymorph was characterized by the following analytical data.

Differential Scanning Colorimetry (DSC):

Endotherm at 252.33° C. (onset at 246.19° C.) exotherm at 205.0 (onsetat 200.68° C.) and 259.00° C. (onset at 255.83° C.).

X-ray powder diffraction:

(2θ values): 11.16±0.2, 12.06±0.2, 13.74±0.2, 15.06±0.2, 16.46±0.2,18.60±0.2, 21.72±0.2, 22.44±0.2, 23.72±0.2, 24.66±0.2, 25.90±0.2,30.08±0.2, 32.58 ±0.2.

IR values (cm⁻¹): 3442, 2957, 1728, 1623, 1512, 1460, 1318, 1277, 1184,1056, 938.

Example 104 Crystalline polymorphic form of(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride—Polymorph A2

3 gm of(±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride salt was dissolved in 15 ml of water at refluxtemperature, allowed to crystallize by cooling to a temperature between25-35° C. and filtered under suction. The solid obtained was furtherdried at 70° C. under vacuum to provide crystalline material (2.8 gm).

The polymorph was characterized by the following analytical data.

Differential Scanning Colorimetry (DSC):

Endotherm at 144.66 (onset 115.25) and 254.83° C. (onset at 251.00° C.),exotherm at 211.33 (onset at 208.35° C.) and 259.66° C. (onset at257.18° C.).

X-ray powder diffraction:

(2θ values): 8.58±0.2, 13.08±0.2, 14.9±0.2, 16.72±0.2, 18.34±0.2,22.68±0.2, 25.38±0.2, 25.92±0.2, 27.6±0.2, 28.18±0.2.

IR values (cm⁻): 3476, 3332, 2880, 1712, 1619, 1528, 1448, 1329, 1273,1234, 1180, 1066, 1035, 989.

Example 105 Crystalline polymorphic form of(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride—Polymorph A1

30 gm of(−)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride was dissolved in 3.0 liter methanol at refluxtemperature. The clear solution was filtered through a celite bed andthe resultant solution was concentrated to approximately 500 ml, cooledto a temperature between 25-35° C. and filtered under suction. The solidobtained was further dried at 70° C. under vacuum to provide crystallinematerial (24.0 gm).

The polymorph was characterized by the following analytical data.

Differential Scanning Colorimetry (DSC):

Endotherm at 126.5° C. (onset 93.94° C.) and 252.50° C. (onset at245.14° C.), exotherm at 202.83 (onset at 200.02° C.) and 257.17° C.(onset at 255.66° C.).

X-ray powder diffraction: Crystalline nature.

(2θ values): 11.30±0.2, 12.06±0.2, 13.64±0.2, 14.4±0.2, 15.16±0.2,16.48±0.2, 18.52±02, 21.48±0.2, 22.72±0.2, 23.94±0.2, 24.76±0.2,26.42±0.2, 30.24±0.2, 30.60±0.2.

IR values (cm⁻¹): 3363, 2957, 1727, 1625, 1512, 1461, 1377, 1323, 1289,1183, 1056, 942.

Example 106 Crystalline polymorphic form of(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride—Polymorph A2

5 gm of(−)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride was dissolved in 10 ml mixture of 50% aqueousiso-propanol at reflux temperature, cooled to a temperature between25-35° C. and filtered under suction. The solid obtained was furtherdried at 70° C. under vacuum to provide crystalline material (2.78 gm).

The polymorph was characterized by the following analytical data.

Example 107 Crystalline polymorphic form of(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride—Polymorph A1

30 gm of(+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride was dissolved in 3.0 liter methanol at refluxtemperature. The clear solution was filtered through a celite bed andthe resultant solution was concentrated to approximately 500 ml, cooledto a temperature between 25-35° C. and filtered under suction. The solidobtained was further dried at 70° C. under vacuum to provide crystallinematerial (24.0 gm).

The polymorph was characterized by the following analytical data.

Differential Scanning Colorimetry (DSC):

Endotherm at 131.5° C. (onset 92.32° C.) and 253.33° C. (onset at248.28° C.), exotherm at 204.0° C. (onset at 200.8° C.) and 258.0° C.(onset at 256.83° C.).

X-ray powder diffraction: (2θ values): 11.34±0.2, 12.08±0.2, 13.68±0.2,14.44±0.2, 15.18±0.2, 16.50±0.2, 18.56±0.2, 21.50±0.2,22.76±0.2,23.98±0.2, 24.78±0.2, 26.24±0.2, 30.28±0.2, 30.64±0.2,32.52±0.2.

IR values (cm⁻¹): 3653, 3369, 2960, 1727, 1627, 1511, 1465, 1377, 1331,1279, 1183, 1058, 940.

Example 108 Crystalline polymorphic form of(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride—Polymorph A2

5 gm of(+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride was dissolved in 10 ml mixture of 50% aqueousiso-propanol at reflux temperature, cooled to a temperature between25-35° C. and filtered under suction. The solid obtained was furtherdried at 700° C. under vacuum to provide crystalline material (3.40 gm).

The polymorph was characterized by the following analytical data.

Differential Scanning Colorimetry (DSC):

Endotherm at 136.66° C. (onset 101.0° C.) and 256.83° C. (onset at251.92° C.) exotherm at 201.50° C. (onset at 198.60° C.) and 261.16° C.(onset at 259.83° C.).

X-ray powder diffraction:

(2θ values): 7.00±0.2, 7.66±0.2, 8.00±0.2, 12.32±0.2, 12.72±0.2,13.58±0.2, 14.88±0.2, 15.36±0.2, 16.08±0.2, 18.38±0.2, 19.36±0.2,20.58±0.2, 23.18±0.2, 25.40±0.2, 26.72±0.2, 72.82±0.2, 29.80±0.2,30.60±0.2, 32.28±0.2, 36.94±0.2.

IR values (cm⁻¹): 3401, 2845, 2632, 1711, 1621, 1537, 1458, 1378, 1321,1275, 1207, 1061, 989, 806.

BIOLOGICAL EXAMPLES

Microbiological and pharmacological studies can be used to determine therelative potency, and the profile of specificity of the compounds of theinvention as antibacterial agent with a spectrum of activity asdescribed in the specification above.

In the following examples, the compounds of the invention are numberedas per the list of the specific compounds of the invention describedearlier in the text.

Biological Example 1 In-vitro Antimicrobial Tests

The comparative antimicrobial activity of representative compounds, ofthe invention and reference compounds against various sensitive andresistant microorganisms is given in Tables 17 to 20. The test methodwas in accordance with the standard NCCLS protocol (Methods for DilutionAntimicrobial Susceptibility Tests for Bacteria that grow Aerobicially,Approved Standards, M7-A5, Fifth Edition, January 2000).

The antibacterial activities (minimum inhibitory concentration: MIC,mg/ml) were determined by using the two-fold serial agar dilution methodrecommended by NCCLS. The media used for preculture and main culturewere Tryptic Soya broth (Difco) and Mueller Hinton medium (Difco),respectively. The Mueller Hinton agar was supplemented with 5% sheepblood for streptococci. Overnight cultures were diluted with bufferedsaline (pH 7.2) to the final cell density of 5×10⁶-10⁷ CFU/ml, and eachbacterial suspension was applied with a replicator (Denley's multipointinoculator, UK) onto a series of Mueller-Hinton agar plates containingantibacterial agents at various concentrations. Final inoculum wasapproximately 10⁴ CFU/spot. The plates were incubated for 18 hrs at 37°C. The MIC was defined as the lowest concentration of an antibacterialagent that inhibits the development of visible microbial growth on agar.The results obtained are shown in tables 17 to 20.

TABLE 17 Activity Against Fluoroquinolone Sensitive Strains MSSA S.pneumoniae S. sanguis E. faecalis E. coli ATCC ATCC ATCC ATCC ATCC P.aeruginosa Compound 25923 49619 10556* 29212 25922 27853 No. MICs(μg/ml)  1 0.05 0.2 — — 0.05 —  17 0.4 1.56 — — 0.4 —  18 0.05 0.05 0.10.1 0.2 6.25  22 0.05 0.05 0.1 0.1 0.2 6.25  26 0.05 0.1 0.1 0.1 0.26.25  30 0.05 0.1 — — 0.05 —  46 0.05 0.1 — — 0.1 —  48 1.56 >6.25 — —6.25 —  70 0.05 0.2 — — 0.4 —  75 0.05 0.2 — — 0.2 —  92 0.1 — — — 0.05—  93 0.003 0.025 0.05 0.05 0.2 3.12  94 0.003 0.025 0.025 0.1 0.2 3.12 95 0.003 0.025 0.025 0.05 0.2 3.12  97 0.012 0.1 0.2 0.2 0.4 12.5  980.025 0.05 0.025 0.1 0.006 1.56 100 0.025 0.05 0.025 0.1 0.0012 3.12 1020.025 0.025 0.025 0.05 0.025 3.12 106 0.025 0.1 0.1 0.2 0.05 6.25 1100.025 0.025 0.05 0.05 0.025 1.56 114 0.05 0.05 — — 0.05 — 120 0.1 0.8 —— 0.8 — 131 0.8 — — — 1.56 — 133 0.025 0.2 — — 0.4 — 145 0.025 0.4 — —1.56 — 147 <0.006 0.1 — — 0.4 — Levofloxacin 0.2 0.8 1.56 0.8 0.025 3.12Moxifloxacin 0.05 0.2 0.4 0.2 0.05 6.25 *S. sanguis 10556 belongs to thegroup of Viridans Streptococci. 3 other strains of the group S. oralis900, S. salivaris 1062 and S. mitis 1303 provided similar MICs rangingfrom 0.025-0.40 μg/ml in comparison to the reference compounds which hadMIC values ranging from 0.1-3.12.

TABLE 18 Activity Against Fluoroquinolone-Resistant Strains. FQ^(R)Cipro^(R) Cipro^(R) MRSA S. pneumoniae S. sanguis S. mitis 032 718 941938 Compound No. MICs (μg/ml)  18 0.8 0.8 0.4 1.56  22 0.8 0.4 0.2 0.8 26 0.8 0.8 0.4 1.56  93 0.2 0.8 0.4 0.4  94 0.2 0.8 0.4 0.4  95 0.2 0.80.4 0.4  97 0.8 3.12 3.12 3.12  98 1.56 1.56 3.12 1.56 100 1.56 1.563.12 1.56 102 0.8 0.8 1.56 1.56 106 1.56 1.56 6.25 6.25 110 0.4 0.4 1.560.8 Levofloxacin 6.25 12.5 12.5 25.0 Moxifloxacin 3.12 3.12 6.25 6.25

TABLE 19 Activity Against Trovafloxacin-Resistant andVancomycin-Resistant Enterococci Trova-Resist VRE*** MRSE** 110 336Compound No. MICs (μg/ml) 93 0.4 3.12 94 0.4 3.12 95 0.4 3.12 Ref. comp.1* 1.56 6.25 Ref. comp. 2* 1.56 6.25 Ref. comp. 3* 1.56 6.25 *Ref. Comp.1, 2 and 3 are reference compounds cited in our pending U.S patentapplication 09/850,669 and WO 01/85728 Ref. Comp. 1 isS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid (mixture of cis racemate and trans racemate) Ref. Comp. 2 isS-(−)-9-fluoro-6,7-dihydro-8-{cis-4-(RS)-hydroxy-3-(RS)-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid. Ref. Comp. 3 isS-(−)-9-fluoro-6,7-dihydro-8-{trans-4-(RS)-hydroxy-3-(RS)-methylpiperidin-1-yl}-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid **MRSE stands for methicillin-resistant S. epidermidis ***VREstands for vancomycin-resistant Enterococcus faecium

TABLE 20 Activity Against Clinical Isolate MRSA 5076 with Mutations inDNA Gyrase and Topoisomerase IV as well as bearing an Efflux Pump S.aureus MRSA 5076 (sensitive) (triple MRSA 5076 + ATCC 25293 resistance)efflux inhibitor reserpine Compound No. MICs (μg/ml)  18 0.05 3.12 1.56 22 0.05 1.56 1.56  26 0.05 3.12 1.56  95 0.003 0.2 0.2 110 0.05 0.8 0.8Ciprofloxacin 0.8 100 25.0 Moxifloxacin 0.05 12.5 6.25

The data shows that the reference compounds, which although are activeagainst sensitive stapylococci, are rendered quite unattractive due toserious loss in their potency against clinical isolate MRSA 5076expressing triple fluoroquinolone-resistance mechanisms. The folddifference between the MIC values for each compound in the last twocolumns indicates the effect of the efflux pump mechanism on thesusceptibility of the strains to the respective compounds. The compoundsof the invention are 4-fold to 500-fold more potent than the referencecompounds against the resistant strain as seen in column 3.

Resistance to Resistance Development

Compound No. 18 was evaluated in comparison with Moxifloxacin andTrovafloxacin in terms of resistance to resistance development onsequential transfer/passages through respective drug-containing mediaInitially all the three drugs had comparable activity against MRSA 5027(0.4 μg/ml). However, after 10 passages in drug containing medium, MICfor Moxifloxacin and Trovafloxacin was 6.25 μg/ml and 50 μg/mlrespectively, while compound No. 18 showed no elevation and remained 0.4μg/ml. The dates that compound No. 18 has a remarkable property ofresisting the development and selection of MRSA strains resistant to itand is significantly less likely to select resistant mutants in aclinical scenario, thus obviating the risk of treatment failure inpatients.

Biological Example 2 In-vivo Antimicrobial Tests Protocol for SystemicInfection Model

The in vivo efficacy was studied through mouse septicemia model ofinfection in Swiss male and female mice (4 weeks old, 20+2 g weight)using 6 animals in each group. Infective organisms were inoculatedintraperitonially. Compound were administered by oral route 1 hour and 5hours post-infection. By Probit analysis protective doses werecalculated from the survival rate on day 7 in terms of ED₅₀ (50%survival dose) values. Appropriate comparators were included in thestudy.

TABLE 22 In-vivo Activity Against Multidrug-Resistant (MDR) PneumococcalInfections ED₅₀ p.o. (mg/kg) MDR S. pneumoniae COMPOUND 718*  18 30  2220  26 50 100 30 102 30 110 20 Levofloxacin >100 Moxifloxacin >100Gatifloxacin >100 *Resistant to β-lactams, macrolides andfluoroquinolones

Biological Example 3 Acute Toxicity

Each test compound or reference compound was administered orally togroups of 10 swiss mice (body weight: 22-26 gms) each, whereby its acutetoxicity was investigated. The compounds were administered in solutionform. As a result it was found that the median lethal dose (LD₅₀) valuesof compounds 18, 19 and 20 were 650 mg/kg, 600 mg/kg and 650 mg/kgrespectively. The LD₅₀ of reference compound moxifloxacin was 600 mg/kg.On the basis of data of ED₅₀ values (provided in table 22) thetherapeutic index (LD₅₀/ED₅₀) for the test compounds is 3.0 to 7.5 timeshigher than that for moxifloxacin.

Biological Example 4 Cytotoxicity Protocol for cytotoxicity test

Compounds were evaluated for their cytotoxic potential against twocelllines viz. J 744 (mouse macrophage) and V79 (Chinese Hamster Lung).Cells were grown for 3-4days in a culture flask using D-MEM (Dulbecco'sModified Eagle. Medium supplemented with 10% fetal bovine serum (FBS).Freshly grown cells were distributed in microtiter plates at a celldensity of 10⁵-10⁶ cells/well and allowed to alhere and form monolayerby incubating the microtiter plate at 370° C. for 24 hrs. Medium fromeach well was aspirated and replaced with fresh D-MEM (supplemented with2.5% FBS) containing various concentrations of compounds. Following 3hrs. of drug exposure, cell were washed with D-MEM and incubated furtherfor 96 hrs. Cytotoxic effects of drugs were monitored through dailymicroscopic observation and by ascertaining the metabolic status throughredox indicator Alamar blue. Healthy actively metabolising cells bringabout colour change of Alamar blue from blue to pink within an overnightincubation. Cytotoxic drugs inhibit this reaction resulting into bluecoloured well. Minimum drug concentration inhibiting Alamar blue colorchange i.e. resulting into blue coloured wells for a given drug isconsidered cytotoxic concentration.

TABLE 23 J 744 Macrophage V 79 CHL Compound No. (Cytotoxic concentrationmcg/ml)  18 >1000 >1000  22 >1000 1000  26 >1000 >1000  93 >1000 >1000 94 >1000 >1000  95 >1000 >1000  97 >1000 >1000  98 1000 250 100 1000125 102 1000 750 106 >1000 >1000 110 1000 250 Trovafloxacin 500 62.5-120

Biological Example 5 Phototoxicity

Six groups of healthy Swiss Albino mice consisting of 6 males per groupwere orally administered with a single dose of a compound of theinvention or a reference compound at dose levels of 50, 100, 200, 300and 400 mg/kg. The stock solutions for different doses were preparedfreshly on the day of experimentation. Appropriate concentration of eachdose was chosen to give a constant dosage volume of 0.3-0.4 ml/20 g bodyweight of mouse. The treated mice were exposed to UVA light sourceimmediately after dosing for 4 hours and for 4 consecutive days. Themean light intensity in the UVA chamber was adjusted to 0.9-1.2 mW/cm².The total irradiation dose was approximately 18 Joules/cm² /day. Aphototoxic dose is one which causes ear erythema and oeadema. Thephototoxic doses of compounds 18, 19 and 20 of the present inventionwere greater than 500 mg/kg, whereas the phototoxic dose for referencecompound sparfloxacin was 25 mg/kg, thus indicating that the compoundsof the present invention induced no phototoxicity.

1. A compound of Formula I

or its isomers, diastereomers, enantiomers, polymorphs,pseudopolymorphs, salts, hydrates, biohydrolyzable esters, amides andsolvates, wherein R₁ is unsubstituted or substituted C₁₋₅ alkyl,unsubstituted or substituted C₃₋₆ cycloalkyl, or unsubstituted orsubstituted aryl; Y is OR₃ where R₃ is hydrogen, C₁-C₂₀ alkyl, aralkyl,CH₂CH(NH₂)COOH; or R₃ is (CH₂)_(n)—CHR₁₀—OCOR₁₁ or(CH₂)_(n)—CHR₁₀—OCO₂R₁₁ wherein R₁₀ is H, or CH₃; n is 0-3 and R₁₁ isC₁-C₂₀ alkyl, substituted C₁-C₆ alkyl or aralkyl; or R₁₁ is

or R₃ is α-aminoalkanoyl or an alkanoylalkyl group; or R₃ is

 wherein A is CH or N, and when A is CH, Z is NH or NCH₃, and when A isN, Z is CH, O, NH, S, or NCH₃; p is 0-2; q is 0-2; or Y is NHR₂, whereinR₂ is H, C₁₋₂₀ alkyl, unsubstituted or substituted C₃₋₆ cycloalkyl,unsubstituted or substituted aryl, or unsubstituted or substitutedheteroaryl; or R₂ is an amino acid residue derived from one of the 20naturally occurring amino acids, or the optically active isomersthereof, or the racemic mixtures thereof; R₅ is H, C₁₋₅ alkoxy, amino,C₁₋₅ alkylamino, or C₁₋₅ acylamino; Q is —N—, —C(R₈) wherein R₈ is H, F,Cl, bromo, C₁₋₄ alkyl or unsubstituted C₁₋₄ alkoxy; or when Q is CH andthe nitrogen atom to which R₁ is linked forms an optionally substituted5-, 6 or 7-membered ring with the carbon atom of Q, the ring representedby T optionally containing one or more hetero atoms selected fromnitrogen, oxygen or sulfur atoms; X is OR₄, wherein R₄ is hydrogen,C₁-C₂₀ alkyl, glycosyl, aralkyl, C₁-C₆ alkanoyl, aminoalkanoyl or anacid residue derived from one of the 20 naturally occurring amino acids,or the optically active isomers thereof, or the racemic mixturesthereof, or R₄ is 1-aminocyclohexylcarbonyl or COOR₁₁ wherein R₁₁ is asdefined above or R₄ is —CH₂)_(n)—CHR₁₀—OCOOR₁₁ where R₁₀ and R₁₁ are asdefined above, or R₄ is C₆H₁₁O₆, PO₂(CH₃)H, PO₃H₂, PO₂(OCH₃)H or SO₃H;or X is NR₆R₇, wherein R₆ is H, C₁₋₂₀ alkyl, C₃₋₆ cycloalkyl, aralkyl;C₁₋₂₀ alkanoyl, or C₁₋₂₀ alkoxycarbonyl, aralkyloxycarbonyl,amino(C₁₋₂₀)alkanoyl, or an amino acid residue derived from one of the20 naturally occurring amino acids or the optically active isomersthereof, or the racemic mixtures thereof; or R₆ is COOR₁₁ wherein R₁₁ isas defined above or R₆ is C₆H₁₁O₆; R₇ is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,aralkyl; C₁₋₆ alkanoyl, aralkyloxycarbonyl or amino C₁₋₂₀ alkanoyl; oran amino acid residue derived from one of the 20 naturally occurringamino acids or the optically active isomers thereof, or the racemicmixtures thereof, or R₇ is C₆H₁₁O₆; R₈/R₈′ are substituents at the3/3-position of the piperidino ring and are the same or different andrepresent H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, alkylamino, or aralkyland R₉ is a substituent at the 4-position or 5-position of thepiperidino ring and represents H, C₁₋₆ alkyl, C₁₋₅ alkylamino, C₁₋₃dialkylamino, aryl, aralkyl or a trihaloalkyl with the provisos that 1)Q is not C—CH₃ or C—CH₂CH₃ when X is hydroxy, R1 is cyclopropyl and R₈,R₈′ and R₉ are all hydrogen 2) the heteroatom in the ring T is notsulfur, when X, R₅, R₈, R₈′, and R₉ are all hydrogen and Y is OR₃ whereR₃ is hydrogen 3) a) when R₈, R₈′ and R₅ are hydrogen R₁ is c-propyl andQ is N, or b) when R₈, R₈′ and R₅ are hydrogen R₁ is c-propyl, Q is COMeand R₅ is NH₂ or c ) when R₈, R₈′ and R₅ are hydrogen the ring T ispyrido[1,23-de]-1,4-benzoxazine the X is not NR₆R₇ where R₆ and R₇ arehydrogen or R₆ is CH₃ and R₇ is hydr or R₆ is hydrogen and R₇ is CH₃. 2.A compound of the formula

or its isomers, diastereomers, enantiomers, polymorphs,pseudopolymorphs, salts, hydrates, biohydrolyzable esters, amides andsolvates, wherein X is OR₄, wherein R₄ is hydrogen, C₁-C₂₀ alkyl,glycosyl, aralkyl, C₁-C₆ alkanoyl, aminoalkanoyl or an acid residuederived from one of the 20 naturally occurring amino acids, or theoptically active isomers thereof, or the racemic mixtures thereof, or R₄is 1-aminocyclohexylcarbonyl or COOR₁₁ wherein R₁₁ is as defined aboveor R₄ is —(CH₂)_(n)—CHR₁₀—OCOOR₁₁ where R₁₀ and R₁₁ are as definedabove, or R₄ is C₆H₁₁O₆, PO₂(CH₃)H, PO₃H₂, PO₂(OCH₃)H or SO₃H; or X isNR₆R₇, wherein R₆ is H, C₁₋₂₀ alkyl, C₃₋₆ cycloalkyl, aralkyl; C₁₋₂₀alkanoyl, or C₁₋₂₀ alkoxycarbonyl, aralkyloxycarbonyl,amino(C₁₋₂₀)alkanoyl, or an amino acid residue derived from one of the20 naturally occurring amino acids or the optically active isomersthereof, or the racemic mixtures thereof; or R₆ is COOR₁₁ wherein R₁₁ isas defined above or R₆ is C₆H₁₁O₆; R₇ is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,aralkyl; C₁₋₆ alkanoyl, aralkyloxycarbonyl or amino C₁₋₂₀ alkanoyl; oran amino acid residue derived from one of the 20 naturally occurringamino acids or the optically active isomers thereof, or the racemicmixtures thereof, or R₇ is C₆H₁₁O₆; R₈/R₈′ are substituents at the3/3-position of the piperidino ring and are the same or different andrepresent H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, alkylamino, or aralkyland R₉ is substituent at the 4-position or 5-position of the piperidinoring and represent H, C₁₋₆ alkyl, C₁₋₅ alkylamino, C₁₋₃ dialkylamino,aryl, aralkyl or a trihaloalkyl and U is selected from the moietyselected from:


3. The compound according to claim 1 wherein the 7 position amine isselected from


4. A compound of the formula

or its isomer, diastereomers, enantiomers polymorphs, pseudopolymorphs,salts, hydrates, biohydrolyzable esters, amides and solvates, wherein Xis OR₄, wherein R₄ is C₁-C₂₀ alkyl, glycosyl, aralkyl, C₁-C₆ alkanoyl,aminoalkanoyl or an acid residue derived from one of the 20 naturallyoccurring amino acids, or the optically active isomers thereof, or theracemic mixtures thereof, or R₄ is 1-aminocyclohexylcarbonyl or COOR₁₁wherein R₁₁ is as defined above or R₄ is —(CH₂)_(n)—CHR₁₀—OCOOR₁₁ whereR₁₀ and R₁₁ are as defined above, or R₄ is C₆H₁₁O₆, PO₂(CH₃)H, PO₃H₂,PO₂(OCH₃)H or SO₃H; or X is NR₆R₇, wherein R₆ is H, C₁₋₂₀ alkyl, C₃₋₆cycloalkyl, aralkyl; C₁₋₂₀ alkanoyl, or C₁₋₂₀ alkoxycarbonyl,aralkyloxycarbonyl, amino(C₁₋₂₀)alkanoyl, or an amino acid residuederived from one of the 20 naturally occurring amino acids or theoptically active isomers thereof, or the racemic mixtures thereof; or R₆is COOR₁₁ wherein R₁₁ is as defined above or R₆ is C₆H₁₁O₆; R₇ is H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aralkyl; C₁₋₆ alkanoyl, aralkyloxycarbonylor amino C₁₋₂₀ alkanoyl; or an amino acid residue derived from one ofthe 20 naturally occurring amino acids or the optically active isomersthereof, or the racemic mixtures thereof, or R₇ is C₆H₁₁O₆; R₈/R₈′ aresubstituents at the 3/3-position of the piperidino ring and are the sameor different and represent H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl,alkylamino, or aralkyl and R₉ is a substituent at the 4-position or5-position of the piperidino ring and represents H, C₁₋₆ alkyl, C₁₋₅alkylamino, C₁₋₃ dialkylamino, aryl, aralkyl or a trihaloalkyl.
 5. Acompound selected from the group consisting of:1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (mixture of cis and trans isomers) or its salt;trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (racemic mixture of 4R,3R and 4S,3S) or its salt;trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (4R,3R) or its salt;trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (4S,3S) or its salt;cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (racemic mixture of 4S,3R and 4R,3S) or its salt;cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (4S,3R) or its salt;cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (4R,3S) or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (mixture of cis and trans isomers) or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomers or its salt;1-Ethyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-(2,4-Difluorophenyl)-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate or its polymorph;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate or its polymorph;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate or its polymorph;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate or its polymorph;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate or its polymorph;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate or its polymorph;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-acetylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid and its isomers or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-carbethoxyamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-^(t)-butoxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-benzyloxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-benzyloxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-benzyloxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid, its isomer, or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid, its isomer, or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid, its isomer, or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-diethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Ethyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3,5-trimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-3,5-diethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid, its isomer, or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (mixture of cis and trans isomers) or its salt;trans-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (racemic mixture of 4R,3R and 4S,3S) or its salt;trans-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (4R,3R) or its salt;trans-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (4S,3S) or its salt;cis-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (racemic mixture of 4S,3R and 4R,3S) or its salt;cis-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (4S,3R) or its salt;cis-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid (4R,3S) or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-acetylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethoxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-t-butoxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid orits isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-benzyloxycarbonylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid orits isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid, its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-ethyl-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid, its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-methyl-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid, its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-methyl-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-diethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3,5-trimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-3,5-diethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;(±)-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate or its polymorph;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate or its polymorph;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate or its polymorph;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate or its polymorph;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3carboxylicacid or its salt;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate or its polymorph;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate or its polymorph;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-methylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid and its isomers or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-dimethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid and its isomers or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-ethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid and its isomers or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-dimethylamino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid and its isomers or its salt;1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-amino-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and its isomers or its salt;1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and its isomers or its salt;cis/trans-1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;(±)-1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;trans-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;(±)-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;(+)-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;(−)-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-ethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-1-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-n-propyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-isopropyl1-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid or its isomer or itssalt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-isobutyl1-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid or its isomer or itssalt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-aminomethylene-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-aminomethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,3,5-trimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,3,5-trimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-4-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-4-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-4-trifluoromethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid or its isomer orits salt;5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-4-trifluoromethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid or its isomer orits salt;1-Ethyl-6-fluoro-8-methyl-7-(4-amino-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;(±)-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its salt;(+)-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its salt;(−)-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its salt;(±)-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3carboxylicacid or its isomer or its salt;cis-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;(±)-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its salt;(+)-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its salt;(−)-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its salt;(±)-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1,8-Diethyl-6-fluoro-7-(4-amino-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1,8-Diethyl-6-fluoro-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1,8-Diethyl-6-fluoro-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1,8-Diethyl-6-fluoro-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1,8-Diethyl-6-fluoro-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and or its isomer or its salt;cis/trans-1,8-Diethyl-6-fluoro-7(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1,8-Diethyl-6-fluoro-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1,8-Diethyl-6-fluoro-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;(±)-1,8-Diethyl-6-fluoro-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its salt;(+)-1,8-Diethyl-6-fluoro-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its salt;(−)-1,8-Diethyl-6-fluoro-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its salt;(±)-1,8-Diethyl-6-fluoro-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1,8-Diethyl-6-fluoro-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1,8-Diethyl-6-fluoro-7-(4-amino-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;(±)-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its salt;(+)-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its salt;(−)-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its salt;(±)-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt; andcis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt.
 6. A compound selected from the groupconsisting of:(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate or its polymorph;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate or its polymorph;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate or its polymorph;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate or its polymorph;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate or its polymorph;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate or its polymorph;cis/trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis/trans-1-Cyclopropyl-6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt;cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate or its polymorph;(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate or its polymorph;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate or its polymorph;(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate or its polymorph;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid hydrochloride or its polymorph;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid methane sulfonate or its polymorph;(−)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid gluconate or its polymorph or1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-dimethylamino-3-methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylicacid or its isomer or its salt.
 7. A compound of the formula, wherein

Q is C—CH₃ or C—OCH₃; R₈ is H or CH₃; R₈′ or H, CH₃,or C₂H₅; with theproviso that R₈ and R₈′ are not H at the same time; X is OH or NR₆R₇,wherein R₆ and R₇ are the same and are selected from H or CH₃, or itsisomers, diastereomers, enantiomers, polymorphs, pseudopolymorphs,salts, hydrates and solvates.
 8. A compound of the formula wherein

R₁ is C₂H₅, or c-C₃H₇, 2,4-difluorophenyl; R₅ is H or NH₂; Q is C—CH₃,C—C₂H₅, or C—OCH₃; R₈ is H or C₁₋₂ alkyl; R₈′ is H or substituted orunsubstituted C₁₋₄ unbranched or branched alkyl; R₉ is 4-CF₃, 5-H,5-CH₃, or 5-C₂H₅; X is OH, or NR₆R₇ where R₆ is H or methyl; R₇ is H,C₁₋₃ alkyl or cycloalkyl, C₂ alkanoyl; C₂₋₄ unbranched or branchedalkoxycarbonyl or aralkoxycarbonyl or its isomers, diastereomers,enantiomers, polymorphs, pseudopolymorphs, salts, hydrates, andsolvates.
 9. A composition comprising a compound according to claim 1and an excipient, diluent, solvent or carrier.
 10. A compositioncomprising a compound according to claim 5 and an excipient, diluent,solvent or carrier.
 11. A method for treating a systemic or topicalinfection comprising administering an effective amount of a compoundaccording to claim 1 to a patient in need thereof.
 12. A method fortreating a systemic or topical infection comprising administering aneffective amount of a compound according to claim 5 to a patient in needthereof.
 13. A method for preventing a systemic or topical infectioncomprising administering and effective amount of a compound according toclaim 1 to a patient at risk for developing the infection.
 14. A methodfor preventing a systemic or topical infection comprising administeringan effective amount of a compound according to claim 5 to a patient atrisk for developing the infection.